Therapeutic compounds and compositions

ABSTRACT

Compounds of general formula (I) and compositions comprising compounds of general formula (I) that modulate pyruvate kinase are described herein. Also described herein are methods of using the compounds that modulate pyruvate kinase in the treatment of diseases.

CLAIM OF PRIORITY

This application claims priority from International Application SerialNo. PCT/CN2013/072688, filed Mar. 15, 2013 which is incorporated hereinby reference in its entirety.

BACKGROUND OF INVENTION

Pyruvate kinase deficiency (PKD) is one of the most common enzymedefects in erythrocytes in human due to autosomal recessive mutations ofthe PKLR gene (Zanella, A., et al., Br J Haematol 2005, 130 (1), 11-25).It is also the most frequent enzyme mutation in the central glycolyticpathway and only second to glucose-6 phosphate dehydrogenase (G6PD)deficiency (Kedar, P., et al., Clin Genet 2009, 75 (2), 157-62) of thehexose monophosphate shunt.

Human erythrocytes are unique in that they anucleate when mature.Immature erythrocytes have nuclei but during early erythropoiesis priorto becoming circulating reticulocytes they extrude nuclei as well asother organelles such as mitochondria, endoplasmic reticulum, and golgiaparatus, in order to make room for oxygen-carrying hemoglobin. As aresult of lacking mitochondria, mature red blood cells do not utilizeany of the oxygen they transport to economically synthesize adenosinetriphosphate (ATP) as other normal differentiated cells do. Instead, redblood cells depend entirely on anaerobic glycolysis to cyclenicotinamide adenine dinucleotide (NAD⁺) and to make ATP, an essentialenergy source largely used to drive ATPase-dependent K⁺/Na⁺ and Ca²⁺pumps, in order to maintain cell membrane integrity and pliability asthey navigate through blood vessels. In PKD disorder, two majordistinctive metabolic abnormalities are ATP depletion and concomitantincrease of 2,3-diphosphoglycerate consistent with accumulation of upperglycolytic intermediates. Moreover, one of the consequences of decreasedATP and pyruvate level is lowered lactate level leading to inability toregenerate NAD⁺ through lactate dehydrogenase for further use inglycolysis. The lack of ATP disturbs the cation gradient across the redcell membrane, causing the loss of potassium and water, which causescell dehydration, contraction, and crenation, and leads to prematuredestruction and diminished lifetime of the red blood cells (RBCs). Suchdefective RBCs are destroyed in the spleen, and excessive hemolysis ratein the spleen leads to the manifestation of hemolytic anemia. The exactmechanism by which PKD sequesters newly matured RBCs in the spleen toeffectively shorten overall half-lives of circulating RBCs is not yetclear, but recent studies suggest that metabolic dysregulation affectsnot only cell survival but also the maturation process resulting inineffective erythropoiesis (Aizawa, S. et al., Exp Hematol 2005, 33(11), 1292-8).

Pyruvate kinase catalyzes the transfer of a phosphoryl group fromphosphoenolpyruvate (PEP) to ADP, yielding one molecule of pyruvate andone molecule of ATP. The enzyme has an absolute requirement for Mg²⁺ andK⁺ cations to drive catalysis. PK functions as the last critical step inglycolysis because it is an essentially irreversible reaction underphysiological conditions. In addition to its role of synthesizing one ofthe two ATP molecules from the metabolism of glucose to pyruvate,pyruvate kinase is also an important cellular metabolism regulator. Itcontrols the carbon flux in lower-glycolysis to provide key metaboliteintermediates to feed biosynthetic processes, such as pentose-phosphatepathway among others, in maintaining healthy cellular metabolism.Because of these critical functions, pyruvate kinase is tightlycontrolled at both gene expression and enzymatic allostere levels. Inmammals, fully activated pyruvate kinase exists as a tetrameric enzyme.Four different isozymes (M1, M2, L and R) are expressed from twoseparate genes. Erythrocyte-specific isozyme PKR is expressed from thePKLR gene (“L gene”) located on chromosome 1q21. This same gene alsoencodes the PKL isozyme, which is predominately expressed in the liver.PKLR consists of 12 exons with exon 1 is erythroid-specific whereas exon2 is liver-specific. The two other mammalian isozymes PKM1 and PKM2 areproduced from the PKM gene (“M gene”) by alternative splicing eventscontrolled by hnRNP proteins. The PKM2 isozyme is expressed in fetaltissues and in adult proliferating cells such as cancer cells. Both PKRand PKM2 are in fact expressed in proerythroblasts. However, uponerythroid differentiation and maturation, PKM2 gradually is decreased inexpression and progressively replaced by PKR in mature erythrocytes.

Clinically, hereditary PKR deficiency disorder manifests asnon-spherocytic hemolytic anemia. The clinical severity of this disorderrange from no observable symptoms in fully-compensated hemolysis topotentially fatal severe anemia requiring chronic transfusions and/orsplenectomy at early development or during physiological stress orserious infections. Most affected individuals who are asymptomatic,paradoxically due to enhanced oxygen-transfer capacity, do not requireany treatment. However, for some of the most severe cases, whileextremely rare population-wise with estimated prevalence of 51 permillion (Beutler, E. Blood 2000, 95 (11), 3585-8), there is nodisease-modifying treatment available for these patients other thanpalliative care (Tavazzi, D. et al., Pediatr Ann 2008, 37 (5), 303-10).These hereditary non-spherocytic haemolytic anemia (HNSHA) patientspresent a clear unmet medical need.

Heterogenous genetic mutations in PKR lead to dysregulation of itscatalytic activity. Since the initial cloning of PKR and report of asingle point mutation Thr³⁸⁴>Met associated with a HNSHA patient (Kanno,H. et al., Proc Natl Acad Sci USA 1991, 88 (18), 8218-21), there are nownearly 200 different reported mutations associated with this diseasereported worldwide (Zanella, A. et al., Br J Haematol 2005, 130 (1),11-25; Kedar, P., et al., Clin Genet 2009, 75 (2), 157-62; Fermo, E. etal., Br J Haematol 2005, 129 (6), 839-46; Pissard, S. et al., Br JHaematol 2006, 133 (6), 683-9). Although these mutations represent widerange genetic lesions that include deletional and transcriptional ortranslational abnormalities, by far the most common type is missensemutation in the coding region that one way or another affects conservedresidues within domains that are structurally important for optimalcatalytic function of PKR. The pattern of mutation prevalence seems tobe unevenly distributed toward specific ethnic backgrounds. Forinstance, the most frequent codon substitutions reported for NorthAmerican and European patients appear to be Arg⁴⁸⁶>Trp and Arg⁵¹⁰>Gln,while mutations Arg⁴⁷⁹>His, Arg⁴⁹⁰>Trp and Asp³³¹>Gly were morefrequently found in Asian patients (Kedar, P., et al., Clin Genet 2009,75 (2), 157-62).

Cancer cells rely primarily on glycolysis to generate cellular energyand biochemical intermediates for biosynthesis of lipids andnucleotides, while the majority of “normal” cells in adult tissuesutilize aerobic respiration. This fundamental difference in cellularmetabolism between cancer cells and normal cells, termed the WarburgEffect, has been exploited for diagnostic purposes, but has not yet beenexploited for therapeutic benefit.

Pyruvate kinase (PK) is a metabolic enzyme that convertsphosphoenolpyruvate to pyruvate during glycolysis. Four PK isoformsexist in mammals: the L and R isoforms are expressed in liver and redblood cells, the M1 isoform is expressed in most adult tissues, and theM2 isoform is a splice variant of M1 expressed during embryonicdevelopment. All tumor cells exclusively express the embryonic M2isoform. A well-known difference between the M1 and M2 isoforms of PK isthat M2 is a low-activity enzyme that relies on allosteric activation bythe upstream glycolytic intermediate, fructose-1,6-bisphosphate (FBP),whereas M1 is a constitutively active enzyme.

All tumor cells exclusively express the embryonic M2 isoform of pyruvatekinase, suggesting PKM2 as a potential target for cancer therapy. PKM2is also expressed in adipose tissue and activated T-cells.Phosphotyrosine peptide binding to PKM2 leads to a dissociation of FBPfrom PKM2 and conformational changes of PKM2 from an active, tetramericform to an inactive form. Compounds that bind to PKM2 and lock theenzyme in the active confirmation will lead to the loss of allostericcontrol of PKM2 needed for shunting biochemical intermediates fromglycolysis into biosynthesis of nucleotides and lipids. Thus, theactivation of PKM2 can inhibit the growth and proliferation of cancercells, activated immune cells, and fat cells. Activation of PKM2 maytherefore be effective in the treatment of cancer, obesity, diabetes,autoimmune conditions, and proliferation-dependent diseases, e.g.,benign prostatic hyperplasia (BPH).

SUMMARY OF INVENTION

Described herein are compounds that activate pyruvate kinase andpharmaceutically acceptable salts, solvates, and hydrates thereof, forexample, compounds that activate PKR and/or PKM2.

Also provided are pharmaceutical compositions comprising a compoundprovided herewith and the use of such compositions in methods oftreating diseases and conditions that are related to pyruvate kinasefunction, e.g., PKR function, and/or PKM2 function (including, e.g.,cancer, diabetes, obesity, autoimmune disorders, and benign prostatichyperplasia (BPH)).

In one embodiment, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted, and the aryl or heteroaryl is optionally fused to anoptionally substituted carbocyclyl or an optionally substitutedheterocyclyl;

X is selected from —NH—S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—CH₂—,—CH₂—S(O)—NH—, —NH—S(O)—CH₂—, —NH—S(O)—, —S(O)—NH—, or —CH₂—S(O)₂—NH—;

Y is C(H) or N; provided that no more than two Y groups are N;

R^(1a) is hydroxyl, —CH₂OH, —CHO, —CO₂H, —N(R^(10a))₂, —CO₂—C₁₋₆ alkyl,—OP(═O)(OH)₂, or —OCO₂—CH₂—OP(═O)(OH)₂;

R^(1b) is C₁₋₈ alkyl optionally substituted with one to four R⁵ groups;C₁₋₈ alkenyl optionally substituted with one to four R⁵ groups;cycloalkyl; heterocycle; aryl; heteroaryl; cycloalkylalkyl;cycloalkylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; aralkyl;aralkenyl; heteroaralkyl; heteroaralkenyl; or —OH, with the proviso thatwhen R^(1a) is OH, R^(1b) is not OH; wherein each cycloalkyl,heterocycle, aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl,heterocyclylalkyl, heterocyclylalkenyl, aralkyl, aralkenyl,heteroaralkyl, or heteroaralkenyl is optionally substituted;

each R² is independently selected from halo, alkyl, CN, OH, and alkoxy,wherein said alkyl or alkoxy is optionally substituted with one to fourR⁵ groups; or

two adjacent R² groups are taken together with the ring atoms they areattached to form a 5- or 6-membered carbocyclic, aryl, heterocyclic orheteroaryl ring;

each R⁴ is independently selected from halo, alkyl, alkoxy, haloalkyl,haloalkoxy and hydroxyl;

each R⁵ is independently selected from halo, OH, C₁₋₆ alkoxy, CN, NH₂,—SO₂—C₁₋₆ alkyl, —NH(C₁₋₆ alkyl), and —N(C₁₋₆ alkyl)₂;

each R^(10a) is independently selected from hydrogen or C₁₋₆ alkyl;

n is 0, 1, 2 or 3; and

m is 0, 1 or 2; provided that a compound of Formula (I) is not thefollowing:

-   (1)    4-[[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;-   (2)    4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;    -   (3)        4-[[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;    -   (4)        4-[[4-(2-fluoro-5-methylphenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;    -   (5)        4-phenyl-1-[4-[(phenylamino)sulfonyl]benzoyl]-4-piperidinecarboxylic        acid methyl ester;    -   (6)        1-[4-[[(2-methylphenyl)amino]sulfonyl]benzoyl]-4-phenyl-4-piperidinecarboxylic        acid methyl ester; or    -   (7)        N-(4-fluorophenyl)-4-[[4-hydroxy-4-(methoxymethyl)-1-piperidinyl]carbonyl]-benzenesulfonamide.

In another embodiment, provided is a method for treating or preventing(e.g., treating) a disease, condition or disorder as described hereincomprising administering a compound provided herein, a pharmaceuticallyacceptable salt, solvate or hydrate thereof, or pharmaceuticalcomposition thereof.

In another embodiment, provided is a method for increasing lifetime ofthe red blood cells (RBCs) in need thereof comprising contacting bloodwith an effective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof; (2) acomposition comprising a compound disclosed herein or a salt, solvate orhydrate thereof and a carrier; or (3) a pharmaceutical compositioncomprising a compound disclosed herein or a pharmaceutically acceptablesalt, solvate or hydrate thereof, and a pharmaceutically acceptablecarrier.

In another embodiment, provided is a method for regulating2,3-diphosphoglycerate levels in blood in need thereof comprisingcontacting blood with an effective amount of (1) a compound disclosedherein or a pharmaceutically acceptable salt, solvate or hydratethereof; (2) a composition comprising a compound disclosed herein or asalt, solvate or hydrate thereof and a carrier; or (3) a pharmaceuticalcomposition comprising a compound disclosed herein or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, and a pharmaceuticallyacceptable carrier.

In another embodiment, provided is a method for treating hereditarynon-spherocytic haemolytic anemia comprising administering to a subjectin need thereof a therapeutically effective amount of (1) a compounddisclosed herein or a pharmaceutically acceptable salt, solvate orhydrate thereof; (2) a pharmaceutical composition comprising a compounddisclosed herein or a pharmaceutically acceptable salt, solvate orhydrate thereof, and a pharmaceutically acceptable carrier.

In another embodiment, provided is a method for treating sickle cellanemia comprising administering to a subject in need thereof atherapeutically effective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof; (2) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier.

In another embodiment, provided is a method for treating hemolyticanemia (e.g., chronic hemolytic anemia caused by phosphoglycerate kinasedeficiency, Blood Cells Mol Dis, 2011; 46(3):206) comprisingadministering to a subject in need thereof a therapeutically effectiveamount of (1) a compound disclosed herein or a pharmaceuticallyacceptable salt, solvate or hydrate thereof; (2) a pharmaceuticalcomposition comprising a compound disclosed herein or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, and a pharmaceuticallyacceptable carrier.

In another embodiment, provided is a method for treating diseases orconditions that are associated with increased 2,3-diphosphoglyceratelevels (e.g., liver diseases (Am J Gastroenterol, 1987; 82(12):1283) andParkinson's (J. Neurol, Neurosurg, and Psychiatry 1976, 39:952)comprising administering to a subject in need thereof a therapeuticallyeffective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof; (2) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier.

In another embodiment, provided is a method for treating thalassemia(e.g., beta-thalassemia), hereditary spherocytosis, hereditaryelliptocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome),paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g.,congenital anemias (e.g., enzymopathies)), or anemia of chronic diseasescomprising administering to a subject in need thereof a therapeuticallyeffective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof; (2) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier.

In another embodiment, provided is a method for treating diseases orconditions that are associated with increased 2,3-diphosphoglyceratelevels (e.g., liver diseases (Am J Gastroenterol, 1987; 82(12):1283) andParkinson's (J. Neurol, Neurosurg, and Psychiatry 1976, 39:952)comprising administering to a subject in need thereof a therapeuticallyeffective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof; (2) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier.

Compounds and compositions described herein are activators of PKRmutants having lower activities compared to the wild type, thus areuseful for methods of the present invention. Such mutations in PKR canaffect enzyme activity (catalytic efficiency), regulatory properties(modulation by fructose bisphosphate (FBP)/ATP), and/or thermostabilityof the enzyme. Examples of such mutations are described in Valentini etal, JBC 2002. Some examples of the mutants that are activated by thecompounds described herein include G332S, G364D, T384M, G37E, R479H,R479K, R486W, R532W, R510Q, and R490W. Without being bound by theory,compounds described herein affect the activities of PKR mutants byactivating FBP non-responsive PKR mutants, restoring thermostability tomutants with decreased stability, or restoring catalytic efficiency toimpaired mutants. The activating activity of the present compoundsagainst PKR mutants may be tested following a method described inExamples 2-5. Compounds described herein are also activators of wildtype PKR.

In an embodiment, to increase the lifetime of the red blood cells, acompound, composition or pharmaceutical composition described herein isadded directly to whole blood or packed cells extracorporeally or beprovided to the subject (e.g., the patient) directly (e.g., by i.p.,i.v., i.m., oral, inhalation (aerosolized delivery), transdermal,sublingual and other delivery routes). Without being bound by theory,compounds described herein increase the lifetime of the RBCs, thuscounteract aging of stored blood, by impacting the rate of release of2,3-DPG from the blood. A decrease in the level of 2, 3-DPGconcentration induces a leftward shift of the oxygen-hemoglobindissociation curve and shifts the allosteric equilibribrium to the R, oroxygenated state, thus producing a therapeutic inhibition of theintracellular polymerization that underlies sickling by increasingoxygen affinity due to the 2,3-DPG depletion, thereby stabilizing themore soluble oxy-hemoglobin. Accordingly, in one embodiment, compoundsand pharmaceutical compositions described herein are useful asantisickling agents. In another embodiment, to regulate2,3-diphosphoglycerate, a compound, composition or pharmaceuticalcomposition described herein is added directly to whole blood or packedcells extracorporeally or be provided to the subject (e.g., the patient)directly (e.g., by i.p., i.v., i.m., oral, inhalation (aerosolizeddelivery), transdermal, sublingual and other delivery routes).

In another embodiment, provided is a method of increasing the level ofPKM2 activity and/or glycolysis in a patient in need thereof. The methodcomprises the step of administering an effective amount of a compounddescribed herein to the patient in need thereof, thereby increasing thelevel of PKM2 activity and/or glycolysis in the patient. In someembodiments, a compound or a composition described herein is used tomaintain PKM2 in its active conformation or activate pyruvate kinaseactivity in proliferating cells as a means to divert glucose metabolitesinto catabolic rather than anabolic processes in the patient.

In another embodiment, provided is a method of inhibiting cellproliferation in a patient in need thereof. The method comprises thestep of administering an effective amount of a compound described hereinto the patient in need thereof, thereby inhibiting cell proliferation inthe patient. In one aspect this method can inhibit growth of atransformed cell, more specifically a cancer cell. In another aspect themethod generally inhibits growth of a PKM2-dependent cell that undergoesaerobic glycolysis.

In another embodiment, provided is a method of treating a patientsuffering from or susceptible to a disease or disorder associated withreduced PKM2 activity or reduced glycolysis in a patient in needthereof. The method comprises the step of administering an effectiveamount of a compound described herein to the patient in need thereof,thereby treating, preventing or ameliorating the disease or disorder inthe patient. In certain embodiment the compound described herein isprovided in a pharmaceutical composition. In certain embodiments, themethod includes the step of identifying or selecting a patient who wouldbenefit from activation of PKM2 prior to treatment. Identifying orselecting such a patient can be on the basis of the level of PKM2activity in a cell of the patient. In one aspect, the selected patientis suffering from or susceptible to unwanted cell growth orproliferation, e.g., cancer, obesity, diabetes, atherosclerosis,restenosis, and autoimmune diseases. In another aspect, the selectedpatient is suffering from a cancer associated with PKM2 function.

In another embodiment, the compound described herein is administered ata dosage and frequency sufficient to increase lactate production oroxidative phosphorylation.

DETAILED DESCRIPTION

The details of construction and the arrangement of components set forthin the following description or illustrated in the drawings are notmeant to be limiting. Embodiments can be practiced or carried out invarious ways. Also, the phraseology and terminology used herein is forthe purpose of description and should not be regarded as limiting. Theuse of “including,” “comprising,” or “having,” “containing”,“involving”, and variations thereof herein, is meant to encompass theitems listed thereafter and equivalents thereof as well as additionalitems.

DEFINITIONS

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” refers to a monovalent hydrocarbon chain that may be astraight chain or branched chain, containing the indicated number ofcarbon atoms. For example, C₁-C₁₂ alkyl indicates that the group mayhave from 1 to 12 (inclusive) carbon atoms in it. In certain aspects,the term “alkyl” refers to a monovalent hydrocarbon chain that may be astraight chain or branched chain, containing 1 to 6 carbon atoms. Inother aspects, the term “alkyl” refers to a monovalent hydrocarbon chainthat may be a straight chain or branched chain, containing 1 to 4 carbonatoms.

The term “haloalkyl” refers to an alkyl in which one or more hydrogenatoms are replaced by halo, and includes alkyl moieties in which allhydrogens have been replaced by halo (e.g., perfluoroalkyl). The term“haloalkoxy” refers to an alkoxy in which one or more hydrogen atoms arereplaced by halo.

The term “alkenyl” refers to a monovalent straight or branchedhydrocarbon chain containing 2-12 carbon atoms and having one or moredouble bonds. Examples of alkenyl groups include, but are not limitedto, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One ofthe double bond carbons may optionally be the point of attachment of thealkenyl substituent. In certain aspects, the term “alkenyl” refers to amonovalent straight or branched hydrocarbon chain containing 2-6 carbonatoms and having one or more double bonds. In other aspects, the term“alkenyl” refers to a monovalent straight or branched hydrocarbon chaincontaining 2-4 carbon atoms and having one or more double bonds.

The term “alkoxy” refers to an —O-alkyl radical.

The term “aryl” refers to a monocyclic, bicyclic, or tricyclic aromatichydrocarbon ring system. Examples of aryl moieties include, but are notlimited to, phenyl, naphthyl, and anthracenyl.

The terms “arylalkyl” or “aralkyl” refer to an alkyl moiety in which analkyl hydrogen atom is replaced by an aryl group. Aralkyl includesgroups in which more than one hydrogen atom has been replaced by an arylgroup. Examples of “arylalkyl” or “aralkyl” include benzyl,2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, and tritylgroups.

The term “carbocyclyl” refers to a non-aromatic, monocyclic, bicyclic,or tricyclic hydrocarbon ring system. Carbocyclyl groups include fullysaturated ring systems (e.g., cycloalkyls), and partially saturated ringsystems.

The term “cycloalkyl” or “carbocyclyl” refers to saturated orunsaturated cyclic, bicyclic, tricyclic, or polycyclic non-aromatichydrocarbon groups having 3 to 12 carbons. Examples of cycloalkylmoieties include, but are not limited to, cyclopropyl, cyclohexyl,methylcyclohexyl, adamantyl, and norbornyl.

The term “heteroaryl” refers to a fully aromatic 5-8 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatomsselected independently from N, O, or S if monocyclic, bicyclic, ortricyclic, respectively).

The term “heterocyclyl” refers to a saturated or unsaturated, 3-10membered non-aromatic monocyclic, 8-12 membered non-aromatic bicyclic,or 11-14 membered non-aromatic tricyclic ring system having 1-3heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively). The heteroatom mayoptionally be the point of attachment of the heterocyclyl substituent.Examples of heterocyclyl include, but are not limited to,tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino,pyrrolinyl, pyrimidinyl, and pyrrolidinyl.

Bicyclic and tricyclic ring systems containing one or more heteroatomsand both aromatic and non-aromatic rings are considered to beheterocyclyl groups according to the present definition. Such bicyclicor tricyclic ring systems are considered to be an aryl or a heteroarylfused to a carbocyclyl or heterocyclyl, where the ring bound to the restof the molecule is required to be aromatic.

The terms “heteroarylalkyl” and “heteroaralkyl”, as used herein, refersto an alkyl group substituted with a heteroaryl group.

The term “heterocyclylalkyl”, as used herein, refers to an alkyl groupsubstituted with a heterocyclyl group.

All ring systems (i.e, aryl, heteroaryl, carbocyclyl, cycloalkyl,heterocyclyl, etc.) or ring system portions of groups (e.g., the arylportion of an aralkyl group) are optionally substituted at one or moresubstitutable carbon atoms with substituents independently selectedfrom: halo, —C≡N, C₁-C₄ alkyl, ═O, C₃₋₇ cycloalkyl, C₁₋₆ alkyl, —OH,—O—(C₁₋₆ alkyl), —SO₂—(C₁₋₆ alkyl), —(C₁₋₄ alkyl)-N(R^(∘))(R^(∘)),—N(R^(∘))(R^(∘)), —O—(C₁₋₄ alkyl)-N(R^(∘))(R^(∘)),—C(O)—N(R^(∘))(R^(∘)), —(C₁₋₄ alkyl)-C(O)—N(R^(∘))R^(∘)),—O-(heteroaryl), —O-(heterocycle), —O-phenyl, -heteroaryl, -heterocycle,and -phenyl, wherein:

-   -   each R^(∘) is independently selected from hydrogen, and —C₁₋₄        alkyl; or    -   two R^(∘)s are taken together with the nitrogen atom to which        they are bound to form a 4- to 8-membered saturated heterocycle        optionally comprising one additional heteroatom selected from N,        S, S(═O), S(═O)₂, and O,    -   any alkyl substituent is optionally further substituted with one        or more of —OH, —O—(C₁₄ alkyl), halo, —NH₂, —NH(C₁₋₄ alkyl), or        —N(C₁₋₄ alkyl)₂; and    -   any carbon atom on a phenyl, cycloalkyl, heteroaryl or        heterocycle substituent is optionally further substituted with        one or more of —(C₁-C₄ alkyl), —(C₁₋₄ fluoroalkyl), —OH,        —O—(C₁₋₄ alkyl), —O—(C₁₋₄ fluoroalkyl), halo, —NH₂, —NH(C₁₋₄        alkyl), or —N(C₁₋₄ alkyl)₂.

All heterocyclyl ring systems (and any heterocyclyl substituents on anyring system) are optionally substituted on one or more any substitutablenitrogen atom with —C₁₋₄ alkyl, or fluoro-substituted C₁₋₄ alkyl.

The term “substituted” refers to the replacement of a hydrogen atom byanother group.

The term “oxo” refers to an oxygen atom, which forms a carbonyl whenattached to carbon, an N-oxide when attached to nitrogen, and asulfoxide or sulfone when attached to sulfur.

The term “selective” in association with a PKM2 activator is meant atleast 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, or 10-fold greateractivation of PKM2 than PKM1.

The term “activator” of pyruvate kinase R as used herein means an agentthat (measurably) increases the activity of wild type pyruvate kinase R(wtPKR) or causes wild type pyruvate kinase R (wt PKR) activity toincrease to a level that is greater than wt PKR's basal levels ofactivity or an agent that (measurably) increases the activity of amutant pyruvate kinase R (mPKR) or causes mutant pyruvate kinase R(mPKR) activity to increase to a level that is greater than that mutantPKR's basal levels of activity, for examples, to a level that is 20%,40%, 50%, 60%, 70%, 80%, 90% or 100% of the activity of wild type PKR.

The term “activator” of pyruvate kinase M2 as used herein means an agentthat (measurably) increases the activity of PKM2 or causes PKM2 activityto increase to a level that is greater than PKM2's basal levels ofactivity. For example, the activator may mimic the effect caused by anatural ligand (e.g., FBP). The activator effect caused by a compoundprovided herein may be to the same, or to a greater, or to a lesserextent than the activating effect caused by a natural ligand, but thesame type of effect is caused. A compound provided herein can beevaluated to determine if it is an activator by measuring eitherdirectly or indirectly the activity of the pyruvate kinase whensubjected to said compound. The activity of PKM2 can be measured, forexample, by monitoring the concentration of a substrate such as ATP orNADH.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl,phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled Standard List of Abbreviations. The abbreviationscontained in said list, and all abbreviations utilized by organicchemists of ordinary skill in the art are hereby incorporated byreference.

Compounds

Provided herein is a compound of Formula (I) or a pharmaceuticallyacceptable salt, solvate or hydrate thereof as described above in theSummary of the Invention, e.g, useful for activating wild type PKRand/or various mutant PKRs such as those mutants described herein,and/or useful for selectively activating PKM2.

In one embodiment, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted, and the aryl or heteroaryl is optionally fused to anoptionally substituted carbocyclyl or an optionally substitutedheterocyclyl;

X is selected from —NH—S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—CH₂—,—CH₂—S(O)—NH—, —NH—S(O)—CH₂—, —NH—S(O)—, —S(O)—NH—, or —CH₂—S(O)₂—NH—;

Y is C(H) or N; provided that no more than two Y groups are N;

R^(1a) is hydroxyl, —CH₂OH, —CHO, —CO₂H, —N(R^(10a))₂, —CO₂—C₁₋₆ alkyl,—OP(═O)(OH)₂, or —OCO₂—CH₂—OP(═O)(OH)₂;

R^(1b) is C₁₋₈ alkyl optionally substituted with one to four R⁵ groups;C₁₋₈ alkenyl optionally substituted with one to four R⁵ groups;cycloalkyl; heterocycle; aryl; heteroaryl; cycloalkylalkyl;cycloalkylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; aralkyl;aralkenyl; heteroaralkyl; heteroaralkenyl; or —OH, with the proviso thatwhen R^(1a) is OH, R^(1b) is not OH; wherein each cycloalkyl,heterocycle, aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl,heterocyclylalkyl, heterocyclylalkenyl, aralkyl, aralkenyl,heteroaralkyl, or heteroaralkenyl is optionally substituted;

each R² is independently selected from halo, alkyl, CN, OH, and alkoxy,wherein said alkyl or alkoxy is optionally substituted with one to fourR⁵ groups; or

two adjacent R² groups are taken together with the ring atoms they areattached to form a 5- or 6-membered carbocyclic, aryl, heterocyclic orheteroaryl ring;

each R⁴ is independently selected from halo, alkyl, alkoxy, haloalkyl,haloalkoxy and hydroxyl;

each R⁵ is independently selected from halo, OH, C₁₋₆ alkoxy, CN, NH₂,—SO₂—C₁₋₆ alkyl, —NH(C₁₋₆ alkyl), and —N(C₁₋₆ alkyl)₂;

each R^(10a) is independently selected from hydrogen or C₁₋₆ alkyl;

n is 0, 1, 2 or 3; and

m is 0, 1 or 2; provided that a compound of Formula (I) is not thefollowing:

-   (1)    4-[[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;-   (2)    4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;-   (3)    4-[[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;-   (4)    4-[[4-(2-fluoro-5-methylphenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;-   (5)    4-phenyl-1-[4-[(phenylamino)sulfonyl]benzoyl]-4-piperidinecarboxylic    acid methyl ester;-   (6)    1-[4-[[(2-methylphenyl)amino]sulfonyl]benzoyl]-4-phenyl-4-piperidinecarboxylic    acid methyl ester; or-   (7)    N-(4-fluorophenyl)-4-[[4-hydroxy-4-(methoxymethyl)-1-piperidinyl]carbonyl]-benzenesulfonamide.    In one embodiment, provided herein is a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted, and the aryl or heteroaryl is optionally fused to anoptionally substituted carbocyclyl or an optionally substitutedheterocyclyl;

X is selected from —NH—S(O)₂—, —NH—S(O)₂—CH₂—, —CH₂—S(O)—NH— or—CH₂—S(O)₂—NH—;

Y is C(H) or N; provided that no more than two Y groups are N;

R^(1a) is hydroxyl, —CH₂OH, —CHO, —CO₂H or —CO₂—C₁₋₆ alkyl;

R^(1b) is C₁₋₈ alkyl optionally substituted with one to four R⁵ groups;C₁₋₈ alkenyl optionally substituted with one to four R⁵ groups;cycloalkyl; heterocycle; aryl; heteroaryl; cycloalkylalkyl;cycloalkylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; aralkyl;aralkenyl; heteroaralkyl; heteroaralkenyl; or —OH, with the proviso thatwhen R^(1a) is OH, R^(1b) is not OH; wherein each cycloalkyl,heterocycle, aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl,heterocyclylalkyl, heterocyclylalkenyl, aralkyl, aralkenyl,heteroaralkyl, or heteroaralkenyl is optionally substituted;

each R² is independently selected from halo, alkyl, CN, OH, and alkoxy,wherein said alkyl or alkoxy is optionally substituted with one to fourR⁵ groups; or

two adjacent R² groups are taken together with the ring atoms they areattached to form a 5- or 6-membered carbocyclic, aryl, heterocyclic orheteroaryl ring;

each R⁴ is independently selected from halo, alkyl, alkoxy, haloalkyl,haloalkoxy and hydroxyl;

each R⁵ is independently selected from halo, OH, C₁₋₆ alkoxy, CN, NH₂,—SO₂—C₁₋₆ alkyl, —NH(C₁₋₆ alkyl), and —N(C₁₋₆ alkyl)₂;

n is 0, 1, 2 or 3; and

m is 0, 1 or 2; provided that a compound of Formula (I) is not thefollowing:

-   (1)    4-[[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;-   (2)    4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;-   (3)    4-[[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;-   (4)    4-[[4-(2-fluoro-5-methylphenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;-   (5)    4-phenyl-1-[4-[(phenylamino)sulfonyl]benzoyl]-4-piperidinecarboxylic    acid methyl ester;-   (6)    1-[4-[[(2-methylphenyl)amino]sulfonyl]benzoyl]-4-phenyl-4-piperidinecarboxylic    acid methyl ester;-   (7)    1-[4-[methyl[(4-methylphenyl)sulfonyl]amino]benzoyl]-4-phenyl-4-piperidinecarboxylic    acid;-   (8)    1-[4-[(methylphenylamino)sulfonyl]benzoyl]-4-phenyl-4-piperidinecarboxylic    acid;-   (9)    1-[4-[(cyclopropylamino)sulfonyl]benzoyl]-4-phenyl-4-piperidinecarboxylic    acid; or-   (10)    4-phenyl-1-[4-[[(2-thienylmethyl)amino]sulfonyl]benzoyl]-4-piperidinecarboxylic    acid methyl ester.

In one embodiment, provided is a compound of formula (I), wherein mis 1. In some aspects of these embodiments, R⁴ is hydroxyl.

In one embodiment, provided is a compound of formula (I), wherein m is 0(i.e., there are no R⁴ substituents on the piperidinyl ring) and R^(1a)is hydroxyl, the compound having formula (Ia):

(wherein each Y is CH), or a pharmaceutically acceptable salt thereof,wherein A, X, R^(1b), R² and n are as described for formula (I).

In certain aspects of formula (I) or (Ia), n is 0. In certain aspects offormula (I) or (Ia), n is 1. In a more specific aspect, R² is C₁₋₆ alkyl(e.g., methyl). In another more specific aspect, R² is C₁₋₆ alkoxy(e.g., methoxy). In another more specific aspect, R² is halo (e.g.,fluoro or chloro). In another more specific aspect, R² is C₄ haloalkoxy(e.g., trifluoromethoxy or difluoromethoxy). In another more specificaspect, R² is cyano.

In certain aspects of formula (I) or (Ia), n is 2. In a more specificaspect, two R² moieties, taken together with the atoms to which they areattached, form an optionally substituted cyclyl (e.g., unsubstitutedphenyl, unsubstituted isothiazolyl). In another more specific aspect,each R² moiety is halo (e.g., fluoro).

In certain aspects of formula (I) or (Ia), A is an optionallysubstituted monocyclic aryl. In a more specific aspect, A is anoptionally substituted phenyl (e.g., 2,3-dichlorophenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 3-cyanophenyl, 4-cyanophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 2,3-diamino-4-fluorophenyl). In certainaspects of formula (I) or (Ia), A is an optionally substituted bicyclicaryl. In a more specific aspect, A is an optionally substituted naphthyl(e.g., unsubstituted naphthyl).

In certain aspects of formula (I) or (Ia), A is an optionallysubstituted monocyclic heteroaryl. In a more specific aspect, A is anoptionally substituted pyridyl (e.g., an optionally substituted3-pyridyl or optionally substituted 2-pyridyl). In an even more specificaspect, A is unsubstituted 3-pyridyl. In an even more specific aspect, Ais unsubstituted 2-pyridyl.

In certain aspects of formula (I) or (Ia), A is an optionallysubstituted bicyclic heteroaryl. In a more specific aspect, A is anoptionally substituted quinolin-8-yl (e.g., unsubstitutedquinolin-8-yl). In another more specific aspect, A is substitutedquinolin-8-yl (e.g., 2-fluoroquinolin-8-yl, 3-fluoroquinolin-8-yl,5-fluoroquinolin-8-yl or 6-fluoroquinolin-8-yl). In another morespecific aspect, A is an optionally substituted quinolin-3-yl (e.g.,unsubstituted quinolin-3-yl). In another more specific aspect, A is anoptionally substituted quinolin-5-yl (e.g., unsubstituted quinolin-5-ylor 2-fluoroquinolin-5-yl). In another more specific aspect, A is anoptionally substituted isoquinolin-5-yl (e.g., unsubstitutedisoquinolin-5-yl). In another more specific aspect, A is an optionallysubstituted quinolin-5-yl (e.g., unsubstituted quinolin-5-yl). Inanother more specific aspect, A is substituted quinolin-5-yl (e.g.,2-fluoroquinolin-5-yl). In another more specific aspect, A is anoptionally substituted benzo[1,2,5]oxadiazole (e.g., unsubstitutedbenzo[1,2,5]oxadiazole). In another more specific aspect, A is anoptionally substituted quinoxalin-5-yl (e.g., unsubstitutedquinoxalin-5-yl or 8-hydroxyquinoxalin-5-yl). In another more specificaspect, A is substituted quinoxalin-5-yl (e.g., 8-fluoroquinoxalin-5-ylor 8-hydroxyquinoxalin-5-yl). In another more specific aspect, A is anoptionally substituted chromanyl (e.g., chroman-8-yl). In another morespecific aspect, A is an optionally substituted2,3-dihydrobenzo[b][1,4]dioxinyl (e.g., unsubstituted2,3-dihydrobenzo[b][1,4]dioxin-5-yl). In another more specific aspect, Ais an optionally substituted benzo[d]thiazol-4-yl (e.g., unsubstitutedbenzo[d]thiazol-4-yl, 6-fluorobenzo[d]thiazol-4-yl,7-fluorobenzo[d]thiazol-4-yl, 2-methylbenzo[d]thiazol-4-yl or2-amino-6-fluorobenzo[d]thiazol-4-yl). In another more specific aspect,A is an optionally substituted benzofuranyl (e.g., benzofuran-7-yl). Inanother more specific aspect, A is an optionally substitutedbenzo[1,2,5]thiadiazol-5-yl (e.g., unsubstitutedbenzo[1,2,5]thiadiazol-5-yl). In another more specific aspect, A is anoptionally substituted benzo[1,2,5]thiadiazol-4-yl (e.g., unsubstitutedbenzo[1,2,5]thiadiazol-4-yl). In another more specific aspect, A is anoptionally substituted benzo[c]thiazolyl (e.g., unsubstitutedbenzo[c]thiazol-4-yl). In another more specific aspect, A is anoptionally substituted 1,2,3,4-tetrahydroquinolin-8-yl (e.g.,unsubstituted 1,2,3,4-tetrahydroquinolin-8-yl). In another more specificaspect, A is an optionally substituted 1H-indol-2(7aH)-on-5-yl (e.g.,1-methyl-1H-indol-2(7aH)-on-5-yl). In another more specific aspect, A isan optionally substituted thieno[3,2-b]pyridin-3-yl (e.g., unsubstitutedthieno[3,2-b]pyridin-3-yl). In another more specific aspect, A is anoptionally substituted benzo[1,3]dioxol-5-yl (e.g., unsubstitutedbenzo[1,3]dioxol-5-yl or 2,2-difluorobenzo[1,3]dioxol-5-yl). In anothermore specific aspect, A is an optionally substitutedbenzo[d]thiazol-7-yl (e.g., unsubstituted benzo[d]thiazol-7-yl or6-methylbenzo[d]thiazol-7-yl or 6-fluorobenzo[d]thiazol-7-yl). Inanother more specific aspect, A is an optionally substitutedcinnolin-8-yl (e.g., unsubstituted cinnolin-8-yl). In another morespecific aspect, A is an optionally substitutedimidazo[1,2-a]pyridine-8-yl (e.g., unsubstitutedimidazo[1,2-a]pyridine-8-yl). In another more specific aspect, A is anoptionally substituted thiazolo[5,4-b]pyridin-7-yl (e.g., unsubstitutedthiazolo[5,4-b]pyridine-7-yl). In another more specific aspect, A is anoptionally substituted 1H-pyrrolo[3,2-b]pyridin-3-yl (e.g.,unsubstituted 1H-pyrrolo[3,2-b]pyridin-3-yl). In another more specificaspect, A is an optionally substituted 1H-pyrrolo[2,3-b]pyridin-1-yl(e.g., unsubstituted 1H-pyrrolo[2,3-b]pyridin-1-yl). In another morespecific aspect, A is an optionally substitutedbenzo[d]oxazol-2(3H)-on-6-yl (e.g.,3-methylbenzo[d]oxazol-2(3H)-on-6-yl). In another more specific aspect,A is an optionally substituted benzo[c]isothiazol-7-yl (e.g.,unsubstituted benzo[c]isothiazol-7-yl).

In certain aspects of formula (I), (Ia), or (Ib) A is:

In another embodiment, provided herein is a compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein:

A is aryl or heteroaryl, wherein the aryl or heteroaryl is optionallysubstituted, and the aryl or heteroaryl is fused to an optionallysubstituted carbocyclyl or an optionally substituted heterocyclyl;

R^(1b) is C₁₋₈ alkyl optionally substituted with one to four R⁵ groups;C₁₋₈ alkenyl optionally substituted with one to four R⁵ groups;cycloalkyl; heterocycle; aryl; heteroaryl; cycloalkylalkyl;cycloalkylalkenyl; heterocyclylalkyl; heterocyclylalkenyl; aralkyl;aralkenyl; heteroaralkyl; heteroaralkenyl; or —OH, with the proviso thatwhen R^(1a) is OH, R^(1b) is not OH; wherein each cycloalkyl,heterocycle, aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl,heterocyclylalkyl, heterocyclylalkenyl, aralkyl, aralkenyl,heteroaralkyl, or heteroaralkenyl is optionally substituted;

each R² is independently selected from halo, alkyl, CN, OH, and alkoxy,wherein said alkyl or alkoxy is optionally substituted with one to fourR⁵ groups; or

two adjacent R² groups are taken together with the ring atoms they areattached to form a 5- or 6-membered carbocyclic, aryl, heterocyclic orheteroaryl ring;

each R⁴ is independently selected from halo, alkyl, alkoxy, haloalkyl,haloalkoxy and hydroxyl;

each R⁵ is independently selected from halo, OH, C₁₋₆ alkoxy, CN, NH₂,—SO₂—C₁₋₆ alkyl, —NH(C₁₋₆ alkyl), and —N(C₁₋₆ alkyl)₂;

n is 0, 1, 2 or 3; and

m is 0, 1 or 2.

In certain aspects of formula (I), (Ia), or (Ib) A is:

In certain aspects of formula (I) or (Ia), X is —NH—S(O)₂—,—NH—S(O)₂—CH₂—, or —CH₂—S(O)₂—NH—. In certain aspects of formula (I) or(Ia), X is —NH—S(O)₂—. In an even more specific aspect of formula (I) or(Ib), A is an optionally substituted quinolin-8-yl and X is —NH—S(O)₂—and the compound has the structure set forth in formula (II) or apharmaceutically acceptable salt thereof:

wherein R^(1b), R², R⁴, m and n are as defined for Formula (I).

In an even more specific aspect of formula (Ia) or (Ib), A is anoptionally substituted quinolin-8-yl and X is —NH—S(O)₂— and thecompound has the structure set forth in formula (IIa) or apharmaceutically acceptable salt thereof:

wherein R^(1b), R², and n are as defined for Formula (Ia).

In certain aspects of formula (I) or (Ia), X is —NH—S(O)₂—,—NH—S(O)₂—CH₂—, or —CH₂—S(O)₂—NH—. In certain aspects of formula (I) or(Ia), X is —NH—S(O)₂—. In an even more specific aspect of formula (I) or(Ib), A is an optionally substituted quinoxalin-5-yl and X is —NH—S(O)₂—and the compound has the structure set forth in formula (III) or apharmaceutically acceptable salt thereof:

wherein R^(1b), R², R⁴, m and n are as defined for Formula (I).

In an even more specific aspect of formula (Ia), A is an optionallysubstituted quinoxalin-5-yl and X is —NH—S(O)₂— and the compound has thestructure set forth in formula (IIIa) or a pharmaceutically acceptablesalt thereof:

wherein R^(1b), R², and n are as defined for Formula (Ia).

In certain aspects of formula (I) or (Ia), X is —NH—S(O)₂—,—NH—S(O)₂—CH₂—, or —CH₂—S(O)₂—NH—. In certain aspects of formula (I) or(Ia), X is —NH—S(O)₂—. In an even more specific aspect of formula (I) or(Ib), A is an optionally substituted benzo[d]thiazol-4-yl and X is—NH—S(O)₂— and the compound has the structure set forth in formula (III)or a pharmaceutically acceptable salt thereof:

wherein R^(1b), R², R⁴, m and n are as defined for Formula (I).

In an even more specific aspect of formula (Ia), A is an optionallysubstituted benzo[d]thiazol-4-yl and X is —NH—S(O)₂— and the compoundhas the structure set forth in formula (IIIa) or a pharmaceuticallyacceptable salt thereof:

wherein R^(1b), R², and n are as defined for Formula (Ia).

In certain embodiments of formula (I) or (Ia), A is an optionallysubstituted monocyclic aryl (e.g., optionally substituted phenyl). Insome embodiments, A is 4-chlorophenyl. In some embodiments, A is3-cyanophenyl. In some embodiments, A is 2-chlorophenyl. In someembodiments, A is 4-cyanophenyl. In some embodiments, A is2-trifluoromethylphenyl. In some embodiments, A is4-trifluoromethylphenyl. In some embodiments, A is3-trifluoromethylphenyl. In some embodiments, A is 3-chlorophenyl. Insome embodiments, A is 4-trifluoromethoxyphenyl. In some embodiments, Ais 2,3-dichlorophenyl. In some embodiments, A is 2,4-difluorophenyl. Insome embodiments, A is 3-trifluoromethoxyphenyl.

In certain embodiments of formula (I) or (Ia), A is phenyl substitutedwith two substituents on adjacent carbons which form an optionallysubstituted heterocyclyl or carbocyclyl ring (e.g., resulting in Acomprising a bicycle).

In some embodiments of formula (I), R^(1a) is hydroxyl. In someembodiments of formula (I), R^(1a) is —C(O)H. In some embodiments offormula (I), R^(1a) is —CH₂OH. In some embodiments of formula (I),R^(1a) is —CO₂—C₁₋₆ alkyl (e.g., —CO₂Et). In some embodiments of formula(I), R^(1a) is —CO₂H. In some embodiments of formula (I), R^(1a) is—N(R^(10a))₂. In some embodiments of formula (I), R^(1a) is—OP(═O)(OH)₂. In some embodiments of formula (I), R^(1a) is—OCO₂—CH₂—OP(═O)(OH)₂.

In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIc), (IV), or (IVa), R^(1b) is cycloalkyl, heterocycle, aryl,heteroaryl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclylalkyl,heterocyclylalkenyl, aralkyl, aralkenyl, heteroaralkyl, orheteroaralkenyl, wherein each cycloalkyl, heterocycle, aryl, heteroaryl,cycloalkylalkyl, cycloalkylalkenyl, heterocyclylalkyl,heterocyclylalkenyl, aralkyl, aralkenyl, heteroaralkyl, orheteroaralkenyl is optionally substituted with halo, C₁₋₆ alkyl, —OH,C₁₋₆ alkoxy, —CN, —NH₂, —SO₂—C₁₋₆ alkyl, —NH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)₂, aryl, haloalkyl, or haloalkoxy.

In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), or (IVa), R^(1b) is aryl; heteroaryl; aralkyl; orheteroaralkyl wherein each aryl; heteroaryl; aralkyl; or heteroaralkylis optionally substituted with halo, C₁₋₆ alkyl, —OH, C₁₋₆ alkoxy, —CN,—NH₂, —SO₂—C₁₋₆ alkyl, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, aryl,haloalkyl, or haloalkoxy.

In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), or (IVa), R^(1b) is optionally substituted aralkyl (e.g.,benzyl, 2,3-difluorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl,2-methylbenzyl, 3-methylbenzyl, 2-trifluoromethylbenzyl,3-trifluoromethylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl).

In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), or (IVa), R^(1b) is optionally substituted aryl (e.g.,unsubstituted phenyl, 2-(2-chlorophenyl)phenyl, 4-cyanophenyl,3-cyanophenyl, 2-cyanophenyl, 2-hydroxyphenyl, 2-(methylsulfonyl)phenyl,3-(methylsulfonyl)phenyl, 2-chloro-4-methylphenyl,2-chloro-4-fluorophenyl, 2-chloro-3-fluorophenyl,2-chloro-5-fluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl,2-methylphenyl, 2-fluorophenyl, 2-methoxyphenyl,2-trifluoromethylphenyl, 2-difluorophenyl, 3-methoxyphenyl,3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl,2-trifluoromethoxyphenyl, 3-chlorophenyl, 2-chlorophenyl,3-fluorophenyl, 2-ethylphenyl, 4-fluorophenyl or2-methyl-4-fluorophenyl). In some embodiments of formula (I), (Ia) (Ib),(II), (IIa), (III), (IIIa), (IV), or (IVa), R^(1b) is phenyl, optionallysubstituted with chloro, fluoro, bromo, methyl, ethyl, —CN,difluoromethyl, trifluoromethyl, —OCF₃, —SO₂—CH₃, or —OCH₃.

In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), or (IVa), R^(1b) is optionally substituted heteroaralkyl(e.g., methyl-3-pyridazinyl, methyl-3-pyridyl, methyl-2-pyridyl,3-methyl-methyl-2-pyridyl, 2-fluoro-methyl-3-pyridyl or3-fluoro-methyl-2-pyridyl). In some embodiments of formula (I), (Ia),(Ib), (II), (IIa), (III), (IIIa), (IV), or (IVa), R^(1b) is optionallysubstituted heteroaryl (e.g., 3-fluoro-2-pyridyl, 3-methyl-2-pyridyl,3-fluoro-4-pyridyl, 4-pyridyl, 4-isothiazolyl,3-methyl-4-fluoro-2-pyridyl, 2-chloro-4-pyridyl,4-fluoro-2-methyl-3-pyridyl, 4-fluoro-3-bromo-2-pyridyl,2-methoxy-3-pyridyl, 6-methoxy-2-pyridyl, 6-fluoro-2-pyridyl,6-methyl-2-pyridyl, 2-methyl-3-pyridyl, 6-chloro-2-pyridyl,3-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl,2-fluoro-3-pyridyl, 2-trifluoromethyl-3-pyridyl or6-difluoromethyl-2-pyridyl).

In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), or (IVa), R^(1b) is optionally substituted C₁₋₈ alkyl(e.g., methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, n-butyl,t-pentyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,2-hydroxy-2-methylpropyl, 3-hydroxy-3-methylbutyl,3,3,3-trifluoropropyl, 2-methoxyethyl, 3,3-difluoropropyl, ethoxymethyl,N,N-dimethylmethyl, pyrrollomethyl or 2-hydroxypropyl). In someembodiments of formula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa),(IV), or (IVa), R^(1b) is optionally substituted cycloalkyl (e.g.,cyclopropyl). In some embodiments of formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IV), or (IVa), R^(1b) is optionally substitutedcycloalkylalkyl (e.g., cyclopropylmethyl, 1-methyl-cyclopropylmethyl,cyclobutylmethyl, 2,2-difluorocyclopropylmethyl). In some embodiments offormula (I), (Ia), (Ib), (II), (IIa), (III), (IIIa), (IV), or (IVa),R^(1b) is optionally substituted C₂₋₈ alkenyl (e.g., 2-methyl-2-propenylor 3,3-difluoro-2-propenyl). In some embodiments of formula (I), (Ia),(Ib), (II), (IIa), (III), (IIIa), (IV), or (IVa), R^(1b) is C₁₋₈ alkyloptionally substituted with one to four R⁵ groups (e.g., halo, —OH, C₁₋₆alkoxy, CN, NH₂, —SO₂—C₁₋₆ alkyl, —NH(C₁₋₆ alkyl), and —N(C₁₋₆ alkyl)₂).In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), or (IVa), R^(1b) is C₁₋₈ alkyl optionally substituted withone to four R⁵ groups (e.g., chloro, fluoro, —OH, —OCH₃, —OCH₂CH₃, —CN,—NH₂, —SO₂—CH₃, —SO₂—CH₂CH₃, —NH(CH₃), —N(CH₃)₂, and —N(CH₃)(CH₂CH₃)).

In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), or (IVa), R^(1b) is —NH—R⁵. In some further aspects ofthese embodiments, R⁵ is optionally substituted aryl (e.g.,2-methoxyphenyl). In some further aspects of these embodiments, R⁵ isoptionally substituted aralkyl (e.g., unsubstituted benzyl).

In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), or (IVa), R^(1b) is —NH—C(O)—R⁵. In some further aspectsof these embodiments, R⁵ is optionally substituted heteroaryl (e.g.,unsubstituted 2-pyridyl).

In some embodiments of formula (I), (Ia), (Ib), (II), (IIa), (III),(IIIa), (IV), or (IVa), R^(1b) is:

In yet another embodiment, the compound is selected from any one of thecompounds set forth in Table 1, below:

TABLE 1 Exemplary Compounds of Formula I: Compound # Structure 100

101

102

103

104

105

106

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

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Compounds described herein are useful as activators of PKR mutantshaving lower activities compared to the wild type, thus are useful formethods of the present invention. Such mutations in PKR can affectenzyme activity (catalytic efficiency), regulatory properties(modulation by fructose bisphosphate (FBP)/ATP), and/or thermostabilityof the enzyme. Examples of such mutations are described in Valentini etal, JBC 2002. Some examples of the mutants that are activated by thecompounds described herein include G332S, G364D, T384M, G37E, R479H,R479K, R486W, R532W, R510Q, and R490W. Without being bound by theory,compounds described herein affect the activities of PKR mutants byactivating FBP non-responsive PKR mutants, restoring thermostability tomutants with decreased stability, or restoring catalytic efficiency toimpaired mutants. The activating activity of the present compoundsagainst PKR mutants may be tested following a method described inExample 8. Compounds described herein are also useful as activators ofwild type PKR.

In an embodiment, to increase the lifetime of the red blood cells, acompound, composition or pharmaceutical composition described herein isadded directly to whole blood or packed cells extracorporeally or beprovided to the patient directly (e.g., by i.p., i.v., i.m., oral,inhalation (aerosolized delivery), transdermal, sublingual and otherdelivery routes). Without being bound by theory, compounds describedherein increase the lifetime of the RBCs, thus counteract aging ofstored blood, by impacting the rate of release of 2,3-DPG from theblood. A decrease in the level of 2, 3-DPG concentration induces aleftward shift of the oxygen-hemoglobin dissociation curve and shiftsthe allosteric equilibribrium to the R, or oxygenated state, thusproducing a therapeutic inhibition of the intracellular polymerizationthat underlies sickling by increasing oxygen affinity due to the 2,3-DPGdepletion, thereby stabilizing the more soluble oxy-hemoglobin.Accordingly, in one embodiment, compounds and pharmaceuticalcompositions described herein are useful as antisickling agents. Inanother embodiment, to regulate 2,3-diphosphoglycerate, a compound,composition or pharmaceutical composition described herein is addeddirectly to whole blood or packed cells extracorporeally or be providedto the patient directly (e.g., by i.p., i.v., i.m., oral, inhalation(aerosolized delivery), transdermal, sublingual and other deliveryroutes).

A compound described herein may be an activator of a PKR, for example, awild type (wt), mutated PKR (e.g., R510Q, or R532W). Activities ofexemplary compounds against wt PKR (in an enzymatic or cell based assay)and mutant PKRs are shown in Table 2 as measured by assays in Examples2-5 below. As shown in Table 2, AA refers to an AC₅₀ less than 100 nM,BB refers to an AC₅₀ from 101 nM to 1.00 μM, CC refers to an AC₅₀ fromthan 1.01 μM to 10.00 μM, DD refers to an AC₅₀ greater than 10.01 μM andEE refers to an AC50 that is not available.

TABLE 2 PKR PKR PKR WT Compound R510Q R532W PKR WT Cell Based # AC50(μM) AC50 (μM) AC50 (μM) AC50 (μM) 100 AA AA AA AA 101 AA AA AA AA 102AA AA AA AA 103 AA AA AA AA 104 AA AA AA AA 105 AA AA AA AA 106 EE AA AAAA 108 AA AA AA AA 109 AA AA AA AA 110 AA AA AA AA 111 AA AA AA AA 112AA AA AA BB 113 AA AA AA AA 114 AA AA AA AA 115 AA AA AA AA 116 AA AA AAAA 117 AA AA AA AA 118 BB AA AA AA 119 AA AA AA AA 120 AA AA AA AA 121AA AA AA AA 122 AA AA AA AA 123 AA AA AA AA 124 AA AA AA AA 125 AA AA AAAA 126 AA AA AA AA 127 AA AA AA AA 128 AA AA AA AA 129 AA AA AA AA 130AA AA AA AA 131 AA AA AA AA 132 AA AA AA EE 133 AA AA AA AA 134 AA AA AAAA 135 BB AA AA AA 136 AA AA AA AA 137 AA AA AA AA 138 AA AA AA AA 140AA AA AA AA 141 BB AA AA AA 142 BB AA AA AA 143 AA AA AA AA 144 AA AA AAAA 145 AA AA AA AA 146 BB AA AA AA 147 BB AA AA AA 148 BB AA AA BB 149EE AA AA AA 150 AA AA AA BB 151 AA AA AA AA 152 BB AA AA BB 153 BB AA AAAA 154 AA AA AA AA 155 BB AA AA AA 156 BB AA AA AA 157 BB AA AA AA 158AA AA AA EE 159 BB AA AA AA 160 AA AA AA AA 161 BB AA AA AA 162 BB AA AAAA 163 BB AA AA AA 164 BB AA AA AA 165 BB AA AA AA 166 BB AA AA AA 167AA AA AA AA 168 BB AA AA AA 169 BB AA AA AA 170 BB AA AA BB 171 BB AA AABB 172 AA AA AA AA 173 AA AA AA AA 174 BB AA AA AA 175 BB AA AA AA 176BB AA AA AA 177 BB AA AA AA 178 BB AA AA AA 179 BB AA AA AA 180 BB AA AAAA 181 BB AA AA EE 182 CC EE AA AA 183 BB AA AA AA 184 BB AA AA BB 185BB AA AA BB 186 BB AA AA BB 187 AA AA AA AA 188 BB AA AA EE 189 BB AA AABB 190 BB AA AA BB 191 BB AA AA AA 192 CC AA AA AA 193 BB AA AA AA 194BB AA AA AA 195 BB AA AA AA 196 BB AA AA BB 197 BB AA AA BB 198 BB AA AAEE 199 BB AA AA AA 200 BB BB AA EE 201 BB AA AA EE 202 BB AA AA EE 203BB AA AA AA 204 BB AA AA AA 205 BB AA AA BB 206 CC AA AA AA 207 BB AA AABB 208 BB AA AA EE 209 BB AA AA AA 210 BB AA AA BB 211 BB AA AA BB 212BB AA AA AA 213 BB AA AA AA 214 BB AA AA AA 215 BB AA AA BB 216 BB AA AAEE 217 BB BB AA BB 218 BB AA AA AA 219 BB AA AA EE 220 BB AA AA CC 221BB AA AA EE 222 BB AA AA AA 223 BB AA AA BB 224 CC AA AA BB 225 BB BB AABB 226 BB AA AA BB 227 BB BB BB EE 228 CC AA BB AA 229 BB BB BB BB 230BB BB BB EE 231 CC BB BB EE 232 BB BB BB EE 233 BB BB BB EE 234 BB BB BBEE 235 BB BB BB EE 237 BB BB BB BB 238 CC BB BB EE 239 BB BB BB EE 240BB BB BB EE 241 CC BB BB BB 242 BB BB BB EE 243 CC BB BB AA 244 CC BB BBEE 245 CC BB BB CC 246 CC AA BB EE 247 CC BB BB EE 250 CC BB BB CC 251BB BB BB EE 253 CC BB BB EE 254 BB BB BB EE 255 CC BB BB EE 256 CC BB BBEE 257 CC BB BB EE 258 BB BB BB EE 259 CC BB BB EE 260 CC BB BB CC 261BB BB BB EE 262 BB BB BB EE 263 BB BB BB EE 265 CC BB BB EE 266 CC BB BBEE 267 CC BB BB EE 268 CC BB BB EE 269 CC BB BB EE 270 CC BB BB EE 271CC BB BB EE 272 CC BB BB EE 273 CC BB BB EE 274 CC BB BB EE 275 CC BB BBEE 276 CC BB BB EE 277 CC BB BB EE 278 CC BB BB EE 280 CC BB BB EE 281EE BB BB EE 283 CC BB BB EE 284 CC BB BB EE 285 DD BB BB EE 286 CC BB BBEE 287 EE CC BB EE 288 EE CC BB EE 289 CC BB BB EE 290 CC BB BB EE 292CC CC BB EE 293 CC BB BB EE 294 DD CC CC EE 296 DD CC CC EE 297 CC CC CCEE 298 DD CC CC EE 299 EE EE CC EE 300 DD CC CC EE 301 EE CC CC EE 302DD CC CC EE 303 DD CC CC EE 304 DD CC CC EE 306 DD CC CC EE 307 DD CC CCEE 308 DD CC CC EE 309 DD CC CC EE 310 EE CC CC EE 311 DD CC CC EE 312DD CC CC EE 313 DD DD CC EE 314 DD DD CC EE 315 EE DD CC EE 316 DD DD DDEE 317 EE EE DD EE 318 DD DD DD EE 319 EE DD DD EE 320 DD DD DD EE 321EE DD DD EE 322 DD DD DD EE 323 EE EE DD EE 324 DD DD DD EE 325 EE EE EEEE 326 EE EE EE EE 327 EE CC EE EE 330 CC BB EE EE 331 EE EE EE EE 353BB AA AA AA 368 CC BB BB EE 372 BB BB BB EE 373 BB BB BB EE 376 CC BB BBEE 377 BB AA AA AA 378 CC BB BB EE 379 BB BB BB BB 380 BB BB AA AA 381BB BB AA EE 382 BB BB AA AA 383 BB AA AA AA 384 BB BB BB EE 385 AA AA AAAA 386 BB BB BB EE 387 BB AA AA BB 388 AA AA AA AA 389 AA AA AA AA 390AA AA AA AA 391 AA AA AA AA 392 AA AA AA AA 393 BB AA AA AA 394 BB AA AAAA 395 BB AA AA BB 396 BB BB AA AA 397 AA AA AA AA 398 BB AA AA AA 399AA AA AA AA 400 BB AA AA AA 401 BB AA AA BB 402 AA AA AA AA 403 BB AA BBAA 404 AA AA AA BB 405 BB BB BB BB 406 AA AA AA AA 407 AA AA AA AA 408AA AA AA AA 409 AA AA AA EE 410 DD BB BB EE 411 BB AA BB AA 412 BB AA AABB 413 BB BB BB EE 414 DD CC CC EE 415 CC CC CC EE 416 DD DD CC EE 417DD CC CC EE 418 DD DD CC EE 419 EE DD DD EE 420 AA AA AA AA 421 DD CC CCEE 422 AA AA AA AA 423 BB AA AA AA 424 AA BB AA BB 425 AA BB AA AA 426BB BB BB BB 427 AA AA AA AA 428 BB AA AA AA 429 AA AA AA AA 430 BB AA AABB 431 AA AA AA BB 432 BB AA AA BB 433 BB AA BB BB 434 BB AA BB BB 435AA AA AA BB 436 BB AA BB BB 437 AA AA AA AA 438 CC CC CC EE 439 AA AA AAAA 440 BB BB AA BB 441 CC BB BB EE 442 BB AA AA BB 445 AA AA AA AA 446DD CC CC EE 447 AA AA AA AA 448 BB AA AA AA 449 DD DD DD EE 450 DD DD DDEE 451 AA BB AA BB 452 AA BB AA AA 453 BB BB BB BB 454 AA AA AA AA 455BB AA AA AA 456 AA AA AA AA 457 BB AA AA BB 458 AA AA AA BB 459 BB AA AABB 460 DD DD DD EE 461 BB AA BB BB 462 BB AA BB BB 463 AA AA AA BB 464BB AA BB BB 465 AA AA AA AA 466 DD DD CC EE 467 CC CC CC EE 468 AA AA AAAA 469 BB BB BB CC 470 DD CC CC EE 471 CC BB BB EE 472 CC BB BB EE 473BB AA AA BB 474 CC BB BB EE 475 EE DD DD EE 476 EE CC CC EE 477 CC BB BBEE 478 BB BB BB BB 479 BB AA AA BB 480 BB AA AA BB 481 CC BB CC EE 482AA AA AA AA 483 BB BB AA BB 484 DD CC CC EE 485 DD CC CC EE 486 BB AA AAAA 487 CC CC CC EE 488 DD BB CC EE 489 EE EE AA BB 490 DD CC CC EE 491BB BB BB BB 492 BB BB BB BB 493 AA AA AA AA 494 BB EE EE EE 495 DD CC CCEE 496 DD CC CC EE 497 AA AA AA AA 498 BB AA AA BB 499 BB AA AA BB 500CC BB BB BB 501 BB BB BB BB 502 BB BB BB BB 503 DD BB BB EE 504 CC CC BBEE 505 BB BB BB EE 506 DD CC CC EE 507 DD BB BB EE 508 BB AA AA AA 509DD BB CC EE 510 CC BB BB EE 511 BB AA AA BB 512 BB AA AA BB 513 BB AA AAAA 514 BB AA AA BB 515 BB EE EE BB 516 BB EE EE AA 517 BB EE EE BB 518BB AA AA BB 519 AA AA AA AA 520 BB AA AA BB 521 BB AA AA AA 522 BB AA AAAA 523 CC BB BB BB 524 EE DD DD CC 525 DD EE EE BB 526 BB BB BB AA 527BB BB BB AA 528 BB AA AA BB 529 BB BB EE EE

The compounds described herein can be made using a variety of synthetictechniques, general and specific examples of which are set forth inExample section.

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. Additionally, the various synthetic steps maybe performed in an alternate sequence or order to give the desiredcompounds. Synthetic chemistry transformations and protecting groupmethodologies (protection and deprotection) useful in synthesizing thecompounds described herein are known in the art and include, forexample, those such as described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995), and subsequent editions thereof.

The compounds provided herein may contain one or more asymmetric centersand thus occur as racemates and racemic mixtures, single enantiomers,individual diastereomers and diastereomeric mixtures. All such isomericforms of these compounds are expressly included within the scope. Unlessotherwise indicated when a compound is named or depicted by a structurewithout specifying the stereochemistry and has one or more chiralcenters, it is understood to represent all possible stereoisomers of thecompound. The compounds provided herewith may also contain linkages(e.g., carbon-carbon bonds) or substituents that can restrict bondrotation, e.g., restriction resulting from the presence of a ring ordouble bond. Accordingly, all cis/trans and E/Z isomers are expresslyincluded.

The compounds provided herein (e.g., of Formula I) may also comprise oneor more isotopic substitutions. For example, H may be in any isotopicform, including ¹H, ²H (D or deuterium), and ³H (T or tritium); C may bein any isotopic form, including ¹²C, ¹³C, and ¹⁴C; O may be in anyisotopic form, including ¹⁶O and ¹⁸O; and the like. The compoundsprovided herein may also be represented in multiple tautomeric forms, insuch instances, expressly includes all tautomeric forms of the compoundsdescribed herein, even though only a single tautomeric form may berepresented (e.g., alkylation of a ring system may result in alkylationat multiple sites; all such reaction products are expressly included).All such isomeric forms of such compounds are expressly included. Allcrystal forms of the compounds described herein are expressly included.

The compounds provided herein include the compounds themselves, as wellas their salts and their prodrugs, if applicable. A salt, for example,can be formed between an anion and a positively charged substituent(e.g., amino) on a compound described herein. Suitable anions includechloride, bromide, iodide, sulfate, nitrate, phosphate, citrate,methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt canalso be formed between a cation and a negatively charged substituent(e.g., carboxylate) on a compound described herein. Suitable cationsinclude sodium ion, potassium ion, magnesium ion, calcium ion, and anammonium cation such as tetramethylammonium ion. Examples of prodrugsinclude esters and other pharmaceutically acceptable derivatives, which,upon administration to a subject, are capable of providing activecompounds.

The compounds provided herein may be modified by appending appropriatefunctionalities to enhance selected biological properties, e.g.,targeting to a particular tissue. Such modifications are known in theart and include those which increase biological penetration into a givenbiological compartment (e.g., blood, lymphatic system, central nervoussystem), increase oral availability, increase solubility to allowadministration by injection, alter metabolism and alter rate ofexcretion.

In an alternate embodiment, the compounds described herein may be usedas platforms or scaffolds that may be utilized in combinatorialchemistry techniques for preparation of derivatives and/or chemicallibraries of compounds. Such derivatives and libraries of compounds havebiological activity and are useful for identifying and designingcompounds possessing a particular activity. Combinatorial techniquessuitable for utilizing the compounds described herein are known in theart as exemplified by Obrecht, D. and Villalgrodo, J. M.,Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries, Pergamon-Elsevier ScienceLimited (1998), and include those such as the “split and pool” or“parallel” synthesis techniques, solid-phase and solution-phasetechniques, and encoding techniques (see, for example, Czarnik, A. W.,Curr. Opin. Chem. Bio., (1997) 1, 60. Thus, one embodiment relates to amethod of using the compounds described herein for generatingderivatives or chemical libraries comprising: 1) providing a bodycomprising a plurality of wells; 2) providing one or more compoundsidentified by methods described herein in each well; 3) providing anadditional one or more chemicals in each well; 4) isolating theresulting one or more products from each well. An alternate embodimentrelates to a method of using the compounds described herein forgenerating derivatives or chemical libraries comprising: 1) providingone or more compounds described herein attached to a solid support; 2)treating the one or more compounds identified by methods describedherein attached to a solid support with one or more additionalchemicals; 3) isolating the resulting one or more products from thesolid support. In the methods described above, “tags” or identifier orlabeling moieties may be attached to and/or detached from the compoundsdescribed herein or their derivatives, to facilitate tracking,identification or isolation of the desired products or theirintermediates. Such moieties are known in the art. The chemicals used inthe aforementioned methods may include, for example, solvents, reagents,catalysts, protecting group and deprotecting group reagents and thelike. Examples of such chemicals are those that appear in the varioussynthetic and protecting group chemistry texts and treatises referencedherein.

Methods of Evaluating Compounds

The compounds described herein can be evaluated for ability to modulatePKM2 (e.g., activate PKM2) by methods known in the art. In someembodiments, compounds described herein are evaluated for ability tomodulate PKM2 (e.g., activate PKM2) in serine deficient conditions. Insome embodiments, exemplary methods include contacting the compound witha cell-based assay which allows assessment of the ability to modulate(e.g., activate) PKM2. E.g., the candidate compound can be contactedwith a cell and measuring the consumption of oxygen or production oflactate. A change in cellular phosphoenolpyruvate, a change inglycerol-phosphate, a change in ribose or deoxyribose, a change in lipidsynthesis, or a change in glucose conversion to lipid or nucleic acidsor amino acids or protein can also be used to evaluate a compound forits ability to modulate PKM2 (e.g., activate PKM2). The evaluation couldalso include measuring a change in pyruvate or a determination of analteration in mitochondrial membrane potential, e.g., as measured byfluorescent potentiometric dyes.

PKM1 and PKM2 for use in the screening/testing method may be produced byany method known in the art for expression of recombinant proteins. Forexample, nucleic acids that encode the desired polypeptide may beintroduced into various cell types or cell-free systems for expression.Eukaryotic (e.g., COS, HEK293T, CHO, and NIH cell lines) and prokaryotic(e.g., E. coli) expression systems may be generated in which a PKMsequence is introduced into a plasmid or other vector, which is thenused to transform living cells. Constructs in which the PKM cDNAcontains the entire open reading frame, or biologically active fragmentthereof, are inserted in the correct orientation into an expressionplasmid and may be used for protein expression. Prokaryotic andeukaryotic expression systems allow for the expression and recovery offusion proteins in which the PKM protein is covalently linked to a tagmolecule on either the amino terminal or carboxy terminal side, whichfacilitates identification and/or purification. Examples of tags thatcan be used include hexahistidine, HA, FLAG, and c-myc epitope tags. Anenzymatic or chemical cleavage site can be engineered between the PKMprotein and the tag molecule so that the tag can be removed followingpurification.

The activity of the PKM enzyme measured in the screening/testing assaymay be measured by, e.g., monitoring the concentration of a substrate(e.g., ATP or NADH) present in the reaction mixture. Pyruvate, producedby the enzymatic activity of pyruvate kinase, is converted into lactateby lactate dehydrogenase, which requires the consumption of NADH(NADH→NAD+). Thus, the activity of PKM2 can be indirectly measured bymonitoring the consumption of NADH through, e.g., fluorescence assays.Additionally, the activity of the PKM2 enzyme can be directly monitoredby measuring the production of ATP, as ATP is produced whenphosphoenolpyruvate is converted to pyruvate. Methods for monitoring theamount of substrate in a reaction mixture include, e.g., absorbance,fluorescence, Raman scattering, phosphorescence, luminescence,luciferase assays, and radioactivity.

The screening procedure requires the presence of specific components inthe reaction mixture. Components utilized in the assay include, e.g., anucleoside diphosphate (e.g., ADP), phosphoenolpyruvate, NADH, lactatedehydrogenase, FBP, a reducing agent (e.g., dithiothreitol), a detergent(e.g., Brij 35), glycerol, and a solvent (e.g., DMSO). Exemplaryreaction conditions are found in Table 3.

TABLE 3 Amount in Component of Reaction Condition Activation Assay ADP0.1-5.0 mM Phosphoenolpyruvate 0.1-5.0 mM NADH 10-1000 μM Lactatedehydrogenase 0.1-10 units Fructose-1,6-bisphosphate 0 DTT 0.1-50 mMBrij 35 0.01-1%  Glycerol 0.1-10% Pyruvate Kinase M2 (used for screen)1-100 pg DMSO   1-10%

Compounds useful as PKM2 activators are those that demonstratespecificity and activation of PKM2 enzyme in the absence of FBP to alevel greater than that of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60,65, 70, 75, 80, 85, 90, 95, 99, or 100% in the presence of FBP.Furthermore, compounds can be evaluated in the presence or absence of aphosphotyrosine peptide. Phosphotyrosine peptide binding to PKM2 leadsto a dissociation of FBP from PKM2 and conformational changes of PKM2from an active, tetrameric form to an inactive form. Compounds that bindto PKM2 and lock the enzyme in the active confirmation even in thepresence of a phosphotyrosine peptide will lead to the loss ofallosteric control of PKM2 needed for shunting the biochemicalintermediates from glycolysis into biosynthesis of other intermediates.This, in turn, will lead to inhibition of growth of cancer cells,activated immune cells and fat cells.

Methods of Treatment

In one embodiment, provided is a method for treating or preventing adisease, condition or disorder as described herein (e.g., treating)comprising administering a compound, a pharmaceutically acceptable saltof a compound or pharmaceutical composition comprising a compounddescribed herein (e.g., a compound of formula (I), (Ia), (Ib), (II),(IIa), (III), (IIIa), (IV), (IVa), or in Table 1).

The compounds and compositions described herein can be administered tocells in culture, e.g., in vitro or ex vivo, or to a subject, e.g., invivo, to treat, prevent, and/or diagnose a variety of disorders,including those described herein below.

As used herein, the term “treat” or “treatment” is defined as theapplication or administration of a compound, alone or in combinationwith, a second therapeutic agent to a subject, e.g., a patient, orapplication or administration of the compound to an isolated tissue orcell, e.g., cell line, from a subject, e.g., a patient, who has adisorder (e.g., a disorder as described herein), a symptom of adisorder, with the purpose to cure, heal, alleviate, relieve, alter,remedy, ameliorate, improve or affect the disorder, or one or moresymptoms of the disorder.

As used herein, an amount of a compound effective to treat a disorder,or a “therapeutically effective amount” refers to an amount of thecompound which is effective, upon single or multiple dose administrationto a subject, in treating a cell, or in curing, alleviating, relievingor improving a subject with a disorder beyond that expected in theabsence of such treatment.

As used herein, the term “prevent” is defined as the application oradministration of a compound, alone or in combination with, a secondtherapeutic agent to a subject, e.g., a patient, or application oradministration of the compound to an isolated tissue or cell, e.g., cellline, from a subject, e.g., a patient, who has a predisposition toward adisorder, with the purpose to prevent the occurrence of at least onesymptom of the disorder or to delay onset of at least one symptom of thedisorder).

As used herein, an amount of a compound effective to prevent a disorder,or a “a prophylactically effective amount” of the compound refers to anamount effective, upon single- or multiple-dose administration to thesubject, in preventing or delaying the occurrence of the onset orrecurrence of a disorder or a symptom of the disorder.

As used herein, the term “subject” is intended to include human andnon-human animals. Exemplary human subjects include a human patienthaving a disorder, e.g., a disorder described herein or a normalsubject. The term “non-human animals” includes all vertebrates, e.g.,non-mammals (such as chickens, amphibians, reptiles) and mammals, suchas non-human primates, domesticated and/or agriculturally usefulanimals, e.g., sheep, dog, cat, cow, pig, etc.

Blood Related Conditions

A compound or composition described herein can be used to treat a bloodrelated condition. In one embodiment, provided is a method forincreasing lifetime of the red blood cells (RBCs) in need thereofcomprising contacting blood with an effective amount of (1) a compounddisclosed herein or a pharmaceutically acceptable salt, solvate orhydrate thereof; (2) a composition comprising a compound disclosedherein or a salt, solvate or hydrate thereof and a carrier; or (3) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier.

In another embodiment, provided is a method for regulating2,3-diphosphoglycerate levels in blood in need thereof comprisingcontacting blood with an effective amount of (1) a compound disclosedherein or a pharmaceutically acceptable salt, solvate or hydratethereof; (2) a composition comprising a compound disclosed herein or asalt, solvate or hydrate thereof and a carrier; or (3) a pharmaceuticalcomposition comprising a compound disclosed herein or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, and a pharmaceuticallyacceptable carrier.

In another embodiment, provided is a method for treating hereditarynon-spherocytic haemolytic anemia comprising administering to a subjectin need thereof a therapeutically effective amount of (1) a compounddisclosed herein or a pharmaceutically acceptable salt, solvate orhydrate thereof; (2) a pharmaceutical composition comprising a compounddisclosed herein or a pharmaceutically acceptable salt, solvate orhydrate thereof, and a pharmaceutically acceptable carrier.

In another embodiment, provided is a method for treating sickle cellanemia (e.g., by activating wild type PKR) comprising administering to asubject in need thereof a therapeutically effective amount of (1) acompound disclosed herein or a pharmaceutically acceptable salt, solvateor hydrate thereof; (2) a pharmaceutical composition comprising acompound disclosed herein or a pharmaceutically acceptable salt, solvateor hydrate thereof, and a pharmaceutically acceptable carrier.

In another embodiment, provided is a method for treating hemolyticanemia (e.g., chronic hemolytic anemia caused by phosphoglycerate kinasedeficiency, Blood Cells Mol Dis, 2011; 46(3):206) comprisingadministering to a subject in need thereof a therapeutically effectiveamount of (1) a compound disclosed herein or a pharmaceuticallyacceptable salt, solvate or hydrate thereof; (2) a pharmaceuticalcomposition comprising a compound disclosed herein or a pharmaceuticallyacceptable salt, solvate or hydrate thereof, and a pharmaceuticallyacceptable carrier.

In another embodiment, provided is a method for treating diseases orconditions that are associated with increased 2,3-diphosphoglyceratelevels (e.g., liver diseases (Am J Gastroenterol, 1987; 82(12):1283) andParkinson's (J. Neurol, Neurosurg, and Psychiatry 1976, 39:952)comprising administering to a subject in need thereof a therapeuticallyeffective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof; (2) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier.

In another embodiment, provided is a method for treating thalassemia(e.g., beta-thalassemia), hereditary spherocytosis, hereditaryelliptocytosis, abetalipoproteinemia (or Bassen-Kornzweig syndrome),paroxysmal nocturnal hemoglobinuria, acquired hemolytic anemia (e.g.,congenital anemias (e.g., enzymopathies)), or anemia of chronic diseasescomprising administering to a subject in need thereof a therapeuticallyeffective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof; (2) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier.

In another embodiment, provided is a method for treating diseases orconditions that are associated with increased 2,3-diphosphoglyceratelevels (e.g., liver diseases (Am J Gastroenterol, 1987; 82(12):1283) andParkinson's (J. Neurol, Neurosurg, and Psychiatry 1976, 39:952)comprising administering to a subject in need thereof a therapeuticallyeffective amount of (1) a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof; (2) apharmaceutical composition comprising a compound disclosed herein or apharmaceutically acceptable salt, solvate or hydrate thereof, and apharmaceutically acceptable carrier.

Compounds and compositions described herein are activators of PKRmutants having lower activities compared to the wild type, thus areuseful for methods of the present invention. Such mutations in PKR canaffect enzyme activity (catalytic efficiency), regulatory properties(modulation by fructose bisphosphate (FBP)/ATP), and/or thermostabilityof the enzyme. Examples of such mutations are described in Valentini etal, JBC 2002. Some examples of the mutants that are activated by thecompounds described herein include G332S, G364D, T384M, G37E, R479H,R479K, R486W, R532W, R510Q, and R490W. Without being bound by theory,compounds described herein affect the activities of PKR mutants byactivating FBP non-responsive PKR mutants, restoring thermostability tomutants with decreased stability, or restoring catalytic efficiency toimpaired mutants. The activating activity of the present compoundsagainst PKR mutants may be tested following a method described inExamples 2-5. Compounds described herein are also activators of wildtype PKR.

In an embodiment, to increase the lifetime of the red blood cells, acompound, composition or pharmaceutical composition described herein isadded directly to whole blood or packed cells extracorporeally or beprovided to the subject (e.g., the patient) directly (e.g., by i.p.,i.v., i.m., oral, inhalation (aerosolized delivery), transdermal,sublingual and other delivery routes). Without being bound by theory,compounds described herein increase the lifetime of the RBCs, thuscounteract aging of stored blood, by impacting the rate of release of2,3-DPG from the blood. A decrease in the level of 2,3-DPG concentrationinduces a leftward shift of the oxygen-hemoglobin dissociation curve andshifts the allosteric equilibribrium to the R, or oxygenated state, thusproducing a therapeutic inhibition of the intracellular polymerizationthat underlies sickling by increasing oxygen affinity due to the 2,3-DPGdepletion, thereby stabilizing the more soluble oxy-hemoglobin.Accordingly, in one embodiment, compounds and pharmaceuticalcompositions described herein are useful as antisickling agents.

Neoplastic Disorders

A compound or composition described herein can be used to treat aneoplastic disorder. A “neoplastic disorder” is a disease or disordercharacterized by cells that have the capacity for autonomous growth orreplication, e.g., an abnormal state or condition characterized byproliferative cell growth. Exemplary neoplastic disorders include:carcinoma, sarcoma, metastatic disorders (e.g., tumors arising fromprostate, colon, lung, breast and liver origin), hematopoieticneoplastic disorders, e.g., leukemias, metastatic tumors. Prevalentcancers include: breast, prostate, colon, lung, liver, and pancreaticcancers. Treatment with the compound may be in an amount effective toameliorate at least one symptom of the neoplastic disorder, e.g.,reduced cell proliferation, reduced tumor mass, etc.

The disclosed methods are useful in the prevention and treatment ofcancer, including for example, solid tumors, soft tissue tumors, andmetastases thereof. The disclosed methods are also useful in treatingnon-solid cancers. Exemplary solid tumors include malignancies (e.g.,sarcomas, adenocarcinomas, and carcinomas) of the various organ systems,such as those of lung, breast, lymphoid, gastrointestinal (e.g., colon),and genitourinary (e.g., renal, urothelial, or testicular tumors)tracts, pharynx, prostate, and ovary. Exemplary adenocarcinomas includecolorectal cancers, renal-cell carcinoma, liver cancer, non-small cellcarcinoma of the lung, and cancer of the small intestine.

Without being bound by theory, applicants believe that altered PKM2levels characterize a subset of all types of cancers, without regard totheir cellular nature or location in the body. Thus, the compounds andmethods disclosed herein are useful to treat any type of cancer that ischaracterized by altered PKM2 levels.

Cancer Combination therapies

In some embodiments, a compound described herein is administeredtogether with one or more additional cancer treatments. Exemplary cancertreatments include, for example: chemotherapy, targeted therapies suchas antibody therapies, immunotherapy, and hormonal therapy. Examples ofeach of these treatments are provided below.

Chemotherapy

In some embodiments, a compound described herein is administered withone or morechemotherapies. Chemotherapy is the treatment of cancer withdrugs that can destroy cancer cells. “Chemotherapy” usually refers tocytotoxic drugs which affect rapidly dividing cells in general, incontrast with targeted therapy. Chemotherapy drugs interfere with celldivision in various possible ways, e.g., with the duplication of DNA orthe separation of newly formed chromosomes. Most forms of chemotherapytarget all rapidly dividing cells and are not specific for cancer cells,although some degree of specificity may come from the inability of manycancer cells to repair DNA damage, while normal cells generally can.

Examples of chemotherapeutic agents used in cancer therapy include, forexample, antimetabolites (e.g., folic acid, purine, and pyrimidinederivatives) and alkylating agents (e.g., nitrogen mustards,nitrosoureas, platinum, alkyl sulfonates, hydrazines, triazenes,aziridines, spindle poison, cytotoxic agents, toposimerase inhibitorsand others). Exemplary agents include Aclarubicin, Actinomycin,Alitretinon, Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin,Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Atrasentan,Belotecan, Bexarotene, endamustine, Bleomycin, Bortezomib, Busulfan,Camptothecin, Capecitabine, Carboplatin, Carboquone, Carmofur,Carmustine, Celecoxib, Chlorambucil, Chlormethine, Cisplatin,Cladribine, Clofarabine, Crisantaspase, Cyclophosphamide, Cytarabine,Dacarbazine, Dactinomycin, Daunorubicin, Decitabine, Demecolcine,Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Elsamitrucin,Enocitabine, Epirubicin, Estramustine, Etoglucid, Etoposide,Floxuridine, Fludarabine, Fluorouracil (5FU), Fotemustine, Gemcitabine,Gliadel implants, Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide,Irinotecan, Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomaldoxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine, Lucanthone,Mannosulfan, Masoprocol, Melphalan, Mercaptopurine, Mesna, Methotrexate,Methyl aminolevulinate, Mitobronitol, Mitoguazone, Mitotane, Mitomycin,Mitoxantrone, Nedaplatin, Nimustine, Oblimersen, Omacetaxine, Ortataxel,Oxaliplatin, Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin,Pirarubicin, Pixantrone, Plicamycin, Porfimer sodium, Prednimustine,Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine,Semustine, Sitimagene ceradenovec, Satraplatin, Streptozocin,Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide,Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurin, Tioguanine,Tipifarnib, Topotecan, Trabectedin, Triaziquone, Triethylenemelamine,Triplatin, Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin,Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine,Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or cytotoxicagents described herein.

Because some drugs work better together than alone, two or more drugsare often given at the same time. Often, two or more chemotherapy agentsare used as combination chemotherapy. In some embodiments, thechemotherapy agents (including combination chemotherapy) can be used incombination with a compound described herein.

Targeted Therapy

In some embodiments, a compound described herein is administered withone or more targeted therapies. Targeted therapy constitutes the use ofagents specific for the deregulated proteins of cancer cells. Smallmolecule targeted therapy drugs are generally inhibitors of enzymaticdomains on mutated, overexpressed, or otherwise critical proteins withinthe cancer cell. Prominent examples are the tyrosine kinase inhibitorssuch as Axitinib, Bosutinib, Cediranib, dasatinib, erlotinib, imatinib,gefitinib, lapatinib, Lestaurtinib, Nilotinib, Semaxanib, Sorafenib,Sunitinib, and Vandetanib, and also cyclin-dependent kinase inhibitorssuch as Alvocidib and Seliciclib. Monoclonal antibody therapy is anotherstrategy in which the therapeutic agent is an antibody whichspecifically binds to a protein on the surface of the cancer cells.Examples include the anti-HER2/neu antibody trastuzumab (HERCEPTIN®)typically used in breast cancer, and the anti-CD20 antibody rituximaband Tositumomab typically used in a variety of B-cell malignancies.Other exemplary antibodies include Cetuximab, Panitumumab, Trastuzumab,Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab. Exemplary fusionproteins include Aflibercept and Denileukin diftitox. In someembodiments, the targeted therapy can be used in combination with acompound described herein.

Targeted therapy can also involve small peptides as “homing devices”which can bind to cell surface receptors or affected extracellularmatrix surrounding the tumor. Radionuclides which are attached to thesepeptides (e.g., RGDs) eventually kill the cancer cell if the nuclidedecays in the vicinity of the cell. An example of such therapy includesBEXXAR®.

Immunotherapy

In some embodiments, a compound described herein is administered withone or more immunotherapies. Cancer immunotherapy refers to a diverseset of therapeutic strategies designed to induce the patient's ownimmune system to fight the tumor. Contemporary methods for generating animmune response against tumors include intravesicular BCG immunotherapyfor superficial bladder cancer, and use of interferons and othercytokines to induce an immune response in renal cell carcinoma andmelanoma patients.

Allogeneic hematopoietic stem cell transplantation can be considered aform of immunotherapy, since the donor's immune cells will often attackthe tumor in a graft-versus-tumor effect. In some embodiments, theimmunotherapy agents can be used in combination with a compounddescribed herein.

Hormonal Therapy

In some embodiments, a compound described herein is administered withone or more hormonal therapies. The growth of some cancers can beinhibited by providing or blocking certain hormones. Common examples ofhormone-sensitive tumors include certain types of breast and prostatecancers. Removing or blocking estrogen or testosterone is often animportant additional treatment. In certain cancers, administration ofhormone agonists, such as progestogens may be therapeuticallybeneficial. In some embodiments, the hormonal therapy agents can be usedin combination with a compound described herein.

Obesity and Fat Disorders

A compound or composition described herein can be used to treat orprevent obesity, e.g., in a human subject, e.g., a child or adultsubject. “Obesity” refers to a condition in which a subject has a bodymass index of greater than or equal to 30. Many compounds describedherein can be used to treat or prevent an over-weight condition.“Over-weight” refers to a condition in which a subject has a body massindex of greater or equal to 25.0. The body mass index (BMI) and otherdefinitions are according to the “NIH Clinical Guidelines on theIdentification and Evaluation, and Treatment of Overweight and Obesityin Adults” (1998). Treatment with the compound may be in an amounteffective to alter the weight of the subject, e.g., by at least 2, 5, 7,10, 12, 15, 20, 25, 30, 25, 40, 45, 50, or 55%. Treatment with acompound may be in an amount effective to reduce the body mass index ofthe subject, e.g., to less than 30, 28, 27, 25, 22, 20, or 18. Thecompounds can be used to treat or prevent aberrant or inappropriateweight gain, metabolic rate, or fat deposition, e.g., anorexia, bulimia,obesity, diabetes, or hyperlipidemia (e.g., elevated triglyceridesand/or elevated cholesterol), as well as disorders of fat or lipidmetabolism.

A compound or composition described herein can be administered to treatobesity associated with Prader-Willi Syndrome (PWS). PWS is a geneticdisorder associated with obesity (e.g., morbid obesity).

A compound or composition described herein can be used to reduce bodyfat, prevent increased body fat, reduce cholesterol (e.g., totalcholesterol and/or ratios of total cholesterol to HDL cholesterol),and/or reduce appetite in individuals having PWS associated obesity,and/or reduce comorbidities such as diabetes, cardiovascular disease,and stroke.

Compositions and Routes of Administration

The compositions delineated herein include the compounds delineatedherein (e.g., a compound described herein), as well as additionaltherapeutic agents if present, in amounts effective for achieving amodulation of disease or disease symptoms, including those describedherein.

The term “pharmaceutically acceptable carrier or adjuvant” refers to acarrier or adjuvant that may be administered to a patient, together witha compound provided herewith, and which does not destroy thepharmacological activity thereof and is nontoxic when administered indoses sufficient to deliver a therapeutic amount of the compound.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions provided herewith include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, self-emulsifying drug delivery systems (SEDDS) such asd-α-tocopherol polyethyleneglycol 1000 succinate, surfactants used inpharmaceutical dosage forms such as Tweens or other similar polymericdelivery matrices, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, potassium sorbate,partial glyceride mixtures of saturated vegetable fatty acids, water,salts or electrolytes, such as protamine sulfate, disodium hydrogenphosphate, potassium hydrogen phosphate, sodium chloride, zinc salts,colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,cellulose-based substances, polyethylene glycol, sodiumcarboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, orchemically modified derivatives such as hydroxyalkylcyclodextrins,including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilizedderivatives may also be advantageously used to enhance delivery ofcompounds of the formulae described herein.

The pharmaceutical compositions provided herewith may be administeredorally, parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir, preferably by oraladministration or administration by injection. The pharmaceuticalcompositions provided herewith may contain any conventional non-toxicpharmaceutically-acceptable carriers, adjuvants or vehicles. In somecases, the pH of the formulation may be adjusted with pharmaceuticallyacceptable acids, bases or buffers to enhance the stability of theformulated compound or its delivery form. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intraarticular, intraarterial, intrasynovial,intrasternal, intrathecal, intralesional and intracranial injection orinfusion techniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, or carboxymethyl cellulose or similar dispersing agentswhich are commonly used in the formulation of pharmaceuticallyacceptable dosage forms such as emulsions and or suspensions. Othercommonly used surfactants such as Tweens or Spans and/or other similaremulsifying agents or bioavailability enhancers which are commonly usedin the manufacture of pharmaceutically acceptable solid, liquid, orother dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions provided herewith may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, emulsions and aqueous suspensions,dispersions and solutions. In the case of tablets for oral use, carrierswhich are commonly used include lactose and corn starch. Lubricatingagents, such as magnesium stearate, are also typically added. For oraladministration in a capsule form, useful diluents include lactose anddried corn starch. When aqueous suspensions and/or emulsions areadministered orally, the active ingredient may be suspended or dissolvedin an oily phase is combined with emulsifying and/or suspending agents.If desired, certain sweetening and/or flavoring and/or coloring agentsmay be added.

The pharmaceutical compositions provided herewith may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing a compound providedherewith with a suitable non-irritating excipient which is solid at roomtemperature but liquid at the rectal temperature and therefore will meltin the rectum to release the active components. Such materials include,but are not limited to, cocoa butter, beeswax and polyethylene glycols.

Topical administration of the pharmaceutical compositions providedherewith is useful when the desired treatment involves areas or organsreadily accessible by topical application. For application topically tothe skin, the pharmaceutical composition should be formulated with asuitable ointment containing the active components suspended ordissolved in a carrier. Carriers for topical administration of thecompounds provided herewith include, but are not limited to, mineraloil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier with suitable emulsifying agents. Suitablecarriers include, but are not limited to, mineral oil, sorbitanmonostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,2-octyldodecanol, benzyl alcohol and water. The pharmaceuticalcompositions provided herewith may also be topically applied to thelower intestinal tract by rectal suppository formulation or in asuitable enema formulation. Topically-transdermal patches are alsoincluded.

The pharmaceutical compositions provided herewith may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art.

When the compositions provided herewith comprise a combination of acompound of the formulae described herein and one or more additionaltherapeutic or prophylactic agents, both the compound and the additionalagent should be present at dosage levels of between about 1 to 100%, andmore preferably between about 5 to 95% of the dosage normallyadministered in a monotherapy regimen. The additional agents may beadministered separately, as part of a multiple dose regimen, from thecompounds provided herewith. Alternatively, those agents may be part ofa single dosage form, mixed together with the compounds providedherewith in a single composition.

The compounds described herein can, for example, be administered byinjection, intravenously, intraarterially, subdermally,intraperitoneally, intramuscularly, or subcutaneously; or orally,buccally, nasally, transmucosally, topically, in an ophthalmicpreparation, or by inhalation, with a dosage ranging from about 0.5 toabout 100 mg/kg of body weight, alternatively dosages between 1 mg and1000 mg/dose, every 4 to 120 hours, or according to the requirements ofthe particular drug. The methods herein contemplate administration of aneffective amount of compound or compound composition to achieve thedesired or stated effect. Typically, the pharmaceutical compositionsprovided herewith will be administered from about 1 to about 6 times perday or alternatively, as a continuous infusion. Such administration canbe used as a chronic or acute therapy. The amount of active ingredientthat may be combined with the carrier materials to produce a singledosage form will vary depending upon the host treated and the particularmode of administration. A typical preparation will contain from about 5%to about 95% active compound (w/w). Alternatively, such preparationscontain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specificdosage and treatment regimens for any particular patient will dependupon a variety of factors, including the activity of the specificcompound employed, the age, body weight, general health status, sex,diet, time of administration, rate of excretion, drug combination, theseverity and course of the disease, condition or symptoms, the patient'sdisposition to the disease, condition or symptoms, and the judgment ofthe treating physician.

Upon improvement of a patient's condition, a maintenance dose of acompound, composition or combination provided herewith may beadministered, if necessary. Subsequently, the dosage or frequency ofadministration, or both, may be reduced, as a function of the symptoms,to a level at which the improved condition is retained when the symptomshave been alleviated to the desired level. Patients may, however,require intermittent treatment on a long-term basis upon any recurrenceof disease symptoms.

Patient Selection and Monitoring

The compounds described herein can modulate PKM2. Accordingly, a patientand/or subject can be selected for treatment using a compound describedherein by first evaluating the patient and/or subject to determinewhether the subject is in need of modulation of PKM2, and if the subjectis determined to be in need of modulation of PKM2, then administering tothe subject a compound described herein.

A subject can be evaluated as being in need of modulation of PKM2 usingmethods known in the art, e.g., by measuring the presence and/oractivity of PKM2 in the patient. In some embodiments, the activityand/or level of PKM2 is evaluated in the cancer.

A patient receiving a compound described herein can be monitored, forexample, for improvement in the condition and/or adverse effects.Improvement of a patient's condition can be evaluated, for example, bymonitoring the growth, absence of growth, or regression of the cancer(e.g., a tumor). In some embodiments, the patient is evaluated using aradiological assay or evaluation of hemolytic parameters.

The compounds described herein can activate mutant PKRs. Accordingly, apatient and/or subject can be selected for treatment using a compounddescribed herein by first evaluating the patient and/or subject todetermine whether the subject carries a mutation in PKR (for examples,one of the mutations as described herein), and if the subject isdetermined to be carrying a mutation in PKR thus is in need ofactivation of the activity of the mutant PKR, then optionallyadministering to the subject a compound described herein. A subject canbe evaluated as carrying a mutation in PKR using methods known in theart.

EXAMPLES

In the following examples, the reagents (chemicals) were purchased fromcommercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and ShanghaiChemical Reagent Company), and used without further purification.Nuclear magnetic resonance (NMR) spectra were obtained on a BruckerAMX-400 NMR (Brucker, Switzerland). Chemical shifts were reported inparts per million (ppm, δ) downfield from tetramethylsilane. Massspectra were given with electrospray ionization (ESI) from a Waters LCTTOF Mass Spectrometer (Waters, USA). Microwave reactions were run on anInitiator 2.5 Microwave Synthesizer (Biotage, Sweden).

ABBREVIATIONS LIST General

anhy. anhydrousaq. aqueousMin minute(s)

hr Hour (s)

mL millilitermmol millimole(s)mol mole(s)sat saturateds.m. starting materialMS mass spectrometryNMR nuclear magnetic resonancer.t. (rt) room temperatureTLC thin layer chromatographyHPLC high-performance liquid chromatography

Spectrum

Hz hertzδ chemical shiftJ coupling constants singletd doublett tripletq quartetm multipletbr broadqd quartet of doubletsdquin doublet of quintetsdd doublet of doubletsdt doublet of triplets

Solvents and Reagents

-   CHCl₃ chloroform-   DAST Diethylaminosulfur trifluoride-   DCM dichloromethane-   DMF dimethylformamide-   Et₂O diethyl ether-   EtOH ethyl alcohol-   EtOAc ethyl acetate-   MeOH methyl alcohol-   MeCN acetonitrile-   PE petroleum ether-   THF tetrahydrofuran-   AcOH acetic acid-   HCl hydrochloric acid-   H₂SO₄ sulfuric acid-   NH₄Cl ammonium chloride-   KOH potassium hydroxide-   NaOH sodium hydroxide-   K₂CO₃ potassium carbonate-   Na₂CO₃ sodium carbonate-   TFA trifluoroacetic acid-   Na₂SO₄ sodium sulfate-   NaBH₄ sodium borohydride-   NaHCO₃ sodium bicarbonate-   LiHMDS lithium hexamethyldisilylamide-   NaHMDS sodium hexamethyldisilylamide-   LAH lithium aluminum hydride-   NaBH₄ sodium borohydride-   LDA lithium diisopropylamide-   Et₃N triethylamine-   Py pyridine-   DMAP 4-(dimethylamino)pyridine-   DIPEA N,N-diisopropylethylamine-   DMP Dess Martin periodinane—1,1,1-Triacetoxy-1,1--   NH₄OH dihydro-1,2-benziodoxol-3(1H)-one ammonium hydroxide-   EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   HOBt 1-hydroxybenzotriazole-   HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium-   Xphos 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl-   BINAP 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl-   Togni 3,3-Dimethyl-1-(trifluoromethyl)-1,2-benziodoxole reagent-   BOMCl (chloromethoxy)methyl)benzene-   AIBN 2,2′-Azobis(2-methylpropionitrile)-   MTBE Methyl tertButyl ether-   m-CPBA 3-Chloroperoxybenzoic acid

Example 1 PKM2 Assay Procedure:

-   -   PKM2 stock enzyme solution was diluted in Reaction Buffer    -   2 μL of compound was added into each well first, and then 180 μL        of the Reaction Mix was added.    -   Reaction mixture with compound (without ADP) were incubated for        30 minutes at 4° C.    -   Plates were re-equilibrated to room temperature prior to adding        20 μL ADP to initiate the reaction.    -   Reaction progress was measured as changes in absorbance at 340        nm wavelength at room temperature (25° C.)

Reaction Mix:

PKM2 (50 ng/well), ADP (0.7 mM), PEP (0.15 mM), NADH (180 μM), LDH (2units) in Reaction Buffer

Reaction Buffer:

100 mM KCl, 50 mM Tris pH 7.5, 5 mM MgCl2, 1 mM DTT, 0.03% BSA.

Example 2 PKR Mutant Assay Procedure

-   -   PKR or PKR mutant enzyme solution was diluted in assay buffer.    -   2 μL of test compound was added into wells first, and then 180        μL reaction mix was added.    -   Reactions mixture with test compound was assembled except for        ADP, and plates were stored for 60 minutes at room temperature.    -   20 uL ADP was added to start reaction at room temperature and        reaction progress was measured as changes in absorbance at 340        nm wavelength at room temperature.

Test Compound Preparation:

-   -   Test compound stock was made at 100× concentration in 100% DMSO        (10 mM)    -   1 to 3 dilutions were made for 11 points (i.e. 50 μl of first        concentration added to 100 μl 100% DMSO to yield 3.33 mM, 50 μl        of this added to 100 μl DMSO to yield 1.11 mM, and so forth)    -   1 to 100 dilution into assay (2 μl in 200 μl) yielded starting        concentration of 100 μM, decreasing 3 fold for 11 points.

Assay Buffer:

100 mM KCl, 50 mM Tris 7.5, 5 mM MgCl₂, 1 mM DTT, 0.03% BSA

Reaction Mixture:

PKR mutant enzyme: 80-400 ng/well; ADP: 0.22-1.65 mM; PEP: 0.1-0.5 mM;NADH:180 uM; LDH: 0.5 units (Sigma#59023); DTT: 1 mM; BSA: 0.03%.

Example 3 PKR WT Single Point Percent Activation Assay

A compound described herein was diluted with DMSO and tested at 1 μMconcentration. The enzyme was diluted in 1× Buffer: (100 mM KCl, 50 mMTris 7.5, 5 mM MgCl₂, 1 mM DTT, 0.03% BSA). 2 μL of compound solutionwas first added into wells, and then 180 μL of enzyme solution wasadded. Assays were assembled except for ADP, and plates were stored for60 minutes at RT. 20 μL ADP was added to start the assay and assayoutput was evaluated using OD340 at SpectraMax. The assay was run atroom temperature.

Final Concentration:

PKR wt (100 ng/well), Tris pH 7.5 (50 mM), KCl (100 mM), MgCl₂ (5 mM),ADP (0.48 mM), PEP (0.15 mM), NADH (180 μM), LDH (0.5 units, Sigma59023), DTT (1 mM) and BSA (0.03%).

Example 4 PKR R510Q Single Point Percent Activation Assay

A compound described herein was diluted with DMSO and tested at 1 μMconcentration. The enzyme was diluted in 1× Buffer: (100 mM KCl, 50 mMTris 7.5, 5 mM MgCl₂, 1 mM DTT, 0.03% BSA). 2 μL of compound solutionwas first added into wells, and then 180 μL of enzyme solution wasadded. Assays were assembled except for ADP, and plates were stored for60 minutes at RT. 20 μL ADP was added to start the assay and assayoutput was evaluated using OD340 at SpectraMax. The assay was run atroom temperature.

Final Concentration:

PKR R510Q (40 ng/well), Tris pH 7.5 (50 mM), KCl (100 mM), MgCl₂ (5 mM),ADP (0.2 mM), PEP (0.11 mM), NADH (180 μM), LDH (0.5 units, Sigma59023), DTT (1 mM) and BSA (0.03%).

Example 5 PKR R532W Single Point Percent Activation Assay

A compound described herein was diluted with DMSO and tested at 1 μMconcentration. The enzyme was diluted in 1× Buffer: (100 mM KCl, 50 mMTris 7.5, 5 mM MgCl₂, 1 mM DTT, 0.03% BSA). 2 μL of compound solutionwas first added into wells, and then 180 μL of enzyme solution wasadded. Assays were assembled except for ADP, and plates were stored for60 minutes at RT. 20 μL ADP was added to start the assay and assayoutput was evaluated using OD340 at SpectraMax. The assay was run atroom temperature.

Final Concentration:

PKR R532W (100 ng/well), Tris pH 7.5 (50 mM), KCl (100 mM), MgCl₂ (5mM), ADP (0.36 mM), PEP (0.1 mM), NADH (180 μM), LDH (0.5 units, Sigma59023), DTT (1 mM) and BSA (0.03%).

Example 6 General Procedure 1: 1A

Step A: 4-(quinoline-8-sulfonamido)benzoic acid (1A)

To a solution of 4-aminobenzoic acid (10 g, 73 mmol) in 100 mL ofanhydrous THF was added pyridine (1.15 g, 146 mmol), andquinoline-8-sulfonyl chloride (20 g, 88 mmol) at 0° C. The resultingmixture was stirred at 70° C. overnight. After filtration, the residuewas washed with EtOH and 14 g of title compound was obtained as pureproduct.

¹H NMR (DMSO-d₆) δ: 10.71 (s, 1H), 9.12 (dd, J=4.2, 1.7 Hz, 1H), 8.47(dd, J=7.5, 1.3 Hz, 1H), 8.51 (dd, J=8.3, 1.9 Hz, 1H), 8.29 (dd, J=8.2,1.2 Hz, 1H), 7.62-7.79 (m, 4H), 7.14-7.22 (m, 2H). LC-MS: m/z 329.3(M+H)⁺

General Procedure 2

Step A:

To a solution of the corresponding Aryl Bromide (1.0 eq.) in anhydrousTHF was added a solution of n-BuLi in THF (1.05 eq.) dropwise at −78° C.After the addition, the mixture was stirred at −78° C. for about 0.5hour. Then a solution of Boc-4-piperidone in THF was added dropwise viaa syringe at −78° C. After the addition, the resulting mixture wasstirred at −78° C. under N₂ for 2 h, then allowed to warm to r.t. Thereaction mixture was quenched by satd. NH₄Cl solution, the resultingmixture was extracted with EtOAc (50 mL, 30 mL). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatography(PE/EtOAc) to afford compound 2B.

Step B:

To a solution of compound 2 (1 eq.) in dioxane, was added a solution ofHCl in dioxane (3 eq.), the reaction mixture was stirred at roomtemperature for about 2 hours, when LCMS detected no s.m. The reactionmixture was concentrated to afford the desired product 2C.

Step C:

To a round-bottomed flask was added compound 2C (1 eq.), DMF (5 mL),DIPEA (3.0 eq.), HBTU (1.2 eq.), and 1A (1 eq.) sequentially. Thereaction mixture was stirred at room temperature overnight or until TLCindicated that s.m. was consumed. The mixture was diluted with brine,extracted with ethyl acetate, the organic layer was dried with anhydrousNa₂SO₄, filtered, and filtrate was concentrated. The desired product 2Dwas purified by a standard method.

Compound 142 General Procedure 2, Step CN-(4-(4-(3-fluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.17 (dd, J=4.3, 1.7 Hz, 1H), 8.56 (s, 1H), 8.38(dd, J=7.3, 1.4 Hz, 1H), 8.32 (dd, J=8.4, 1.7 Hz, 1H), 8.06 (dd, J=8.2,1.3 Hz, 1H), 7.69-7.57 (m, 2H), 7.34 (td, J=8.1, 6.2 Hz, 1H), 7.25-7.15(m, 4H), 7.14-7.07 (m, 2H), 6.99 (tdd, J=8.2, 2.5, 0.8 Hz, 1H), 4.60 (s,1H), 3.60 (s, 1H), 3.47 (s, 1H), 3.26 (s, 1H), 2.06 (s, 1H), 1.82 (s,2H), 1.68 (d, J=9.1 Hz, 2H). LC-MS: m/z 506.6 (M+H)⁺.

Compound 126 General Procedure 2, Step CN-(4-(4-hydroxy-4-(2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.17 (dd, J=1.8, 4.1 Hz, 1H), 8.57 (br. s., 1H),8.42-8.30 (m, 2H), 8.06 (dd, J=1.2, 8.2 Hz, 1H), 7.80 (d, J=7.9 Hz, 1H),7.67-7.47 (m, 4H), 7.47-7.36 (m, 1H), 7.16-7.07 (m, 4H), 4.61 (br. s.,1H), 3.58-3.50 (m, 4H), 2.30-1.85 (m, 4H). LC-MS: m/z 556.5 (M+H)⁺

Compound 127 General Procedure 2, Step CN-(4-(4-(2-ethylphenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.18 (dd, J=4.3 Hz, J=1.6 Hz, 1H), 8.63 (br. s.,1H), 8.31-8.43 (m, 2H), 8.07 (dd, J=8.4 Hz, J=1.3 Hz, 1H), 7.60-7.69 (m,2H), 7.30-7.33 (m, 2H), 7.23-7.27 (m, 1H), 7.14-7.23 (m, 3H), 7.07-7.13(m, 2H), 4.58 (br. s., 1H), 3.58 (br. s., 2H), 3.33 (br. s., 1H), 3.01(q, J=7.6 Hz, 2H), 2.03 (d, J=5.9 Hz, 1H), 1.93 (br. s., 2H), 1.69 (br.s., 2H), 1.25 (t, J=7.5 Hz, 3H). LC-MS: m/z 516.1 (M+H)⁺

Compound 138 General Procedure 2, Step CN-(4-(4-(4-fluoro-2-methylphenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.14 (dd, J=1.6, 4.3 Hz, 1H), 8.62 (br. s., 1H),8.39-8.24 (m, 2H), 8.04 (dd, J=1.3, 8.4 Hz, 1H), 7.66-7.52 (m, 2H),7.25-7.02 (m, 5H), 6.86-6.70 (m, 2H), 4.45 (br. s., 1H), 3.50 (br. s.,2H), 3.33-3.20 (m, 1H), 2.52 (s, 3H), 2.05 (d, J=9.1 Hz, 1H), 1.96 (br.s., 2H), 1.84 (br. s., 2H). LC-MS: m/z 520.6 (M+H)⁺

Compound 150 General Procedure 2, Step CN-(4-(4-hydroxy-4-(2-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.16 (dd, J=1.6, 4.3 Hz, 1H), 8.61 (br. s., 1H),8.42-8.26 (m, 2H), 8.05 (dd, J=1.2, 8.2 Hz, 1H), 7.67-7.49 (m, 3H),7.36-7.06 (m, 7H), 4.55 (br. s., 1H), 3.54 (br. s., 1H), 3.48 (s, 2H),3.24 (br. s., 1H), 1.83 (br. s., 2H), 1.76 (br. s., 2H). LC-MS: m/z572.6 (M+H)⁺

Compound 199 General Procedure 2, Step CN-(4-(4-hydroxy-4-(3-(trifluoromethyl)phenyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.15 (dd, J=1.6, 4.3 Hz, 1H), 8.62 (br. s., 1H),8.41-8.27 (m, 2H), 8.10-8.01 (m, 1H), 7.72 (s, 1H), 7.68-7.41 (m, 5H),7.23-7.15 (m, 2H), 7.15-7.02 (m, 2H), 4.54 (br. s., 1H), 3.57 (br. s.,1H), 3.47 (s, 1H), 3.23 (br. s., 1H), 2.12-1.91 (m, 2H), 1.80 (hr. s.,2H), 1.68 (br. s., 1H). LC-MS: m/z 556.6 (M+H)⁺

Compound 177 General Procedure 2, Step CN-(4-(4-(3-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.13 (dd, J=1.6, 4.3 Hz, 1H), 8.63 (br. s., 1H),8.31 (dd, J=1.5, 10.6 Hz, 1H), 8.37-8.23 (m, 1H), 8.03 (dd, J=1.2, 8.2Hz, 1H), 7.65-7.51 (m, 2H), 7.44-7.35 (m, 1H), 7.27-7.10 (m, 5H),7.10-7.01 (m, 2H), 4.45 (br. s., 1H), 3.59-3.29 (m, 2H), 3.17 (br. s.,1H), 1.98-1.61 (br. s., 5H). LC-MS: m/z 522.5 (M+H)⁺

Compound 194 General Procedure 2, Step CN-(4-(4-(4-fluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.16 (dd, J=1.8, 4.1 Hz, 1H), 8.58 (br. s., 1H),8.42-8.24 (m, 2H), 8.06 (dd, J=1.5, 8.2 Hz, 1H), 7.68-7.55 (m, 2H),7.47-7.36 (m, 2H), 7.24-7.16 (m, 2H), 7.13-6.97 (m, 4H), 3.50 (s, 3H),3.19 (s, 1H), 2.06 (s, 1H), 1.79 (br. s., 3H). LC-MS: m/z 506.6 (M+H)⁺

Compound 245 General Procedure 2, Step CN-(4-(4-hydroxy-4-(3-(trifluoromethoxy)phenyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.16 (dd, J=1.8, 4.4 Hz, 1H), 8.67 (br. s., 1H),8.42-8.24 (m, 2H), 8.10-8.00 (m, 1H), 7.68-7.53 (m, 2H), 7.42-7.29 (m,3H), 7.24-7.03 (m, 5H), 4.55 (br. s., 1H), 3.57-3.23 (br. s., 3H),2.02-1.80 (br. s., 5H). LC-MS: m/z 572.6 (M+H)⁺

Compound 122 General Procedure 2, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15-9.21 (m, 1H), 8.58 (br. s., 1H), 8.39 (dd,J=7.3, 1.3 Hz, 1H), 8.32 (dd, J=8.3, 1.6 Hz, 1H), 8.06 (dd, J=8.2, 1.2Hz, 1H), 7.59-7.68 (m, 2H), 7.48-7.54 (m, 1H), 7.39 (dd, J=7.5, 1.6 Hz,1H), 7.24-7.29 (m, 2H), 7.18-7.23 (m, 2H), 7.07-7.14 (m, 2H), 3.58-3.29(br. s., 4H), 2.34-1.97 (br. m., 4H). LC-MS: m/z 523.1 (M+H)⁺

Compound 165 General Procedure 2, Step CN-(4-(4-(2-fluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (dd, J=4.3, 1.8 Hz, 1H), 8.59 (br. s.,1H), 8.37 (dd, J=7.4, 1.4 Hz, 1H), 8.31 (dd, J=8.4, 1.6 Hz, 1H), 8.05(dd, J=8.3, 1.3 Hz, 1H), 7.56-7.67 (m, 2H), 7.45 (td, J=8.0, 1.8 Hz,1H), 7.24-7.32 (m, 1H), 7.17-7.23 (m, 2H), 7.00-7.17 (m, 4H), 4.56 (br.s., 1H), 3.54 (br. s., 2H), 3.25 (br. s., 1H), 2.44 (br. s., 1H), 2.25(br. s., 1H), 2.1 (s, 1H), 1.85 (s, 1H). LC-MS: m/z 506.6 (M+H)⁺

Compound 184 General Procedure 2, Step CN-(4-(4-hydroxy-4-(2-methoxyphenyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (br. s., 1H), 8.59 (br. s., 1H), 8.25-8.42(m, 2H), 8.05 (d, J=7.9 Hz, 1H), 7.53-7.69 (m, 2H), 7.04-7.33 (m, 6H),6.89-7.02 (m, 2H), 4.54 (br. s., 1H), 3.91 (s, 3H), 3.55 (br. s., 2H),3.32 (br. s., 1H), 2.20-1.90 (m, 4H). LC-MS: m/z 518.6 (M+H)⁺

Compound 100 General Procedure 2, Step CN-[4-[4-(2,3-difluorophenyl)-4-hydroxy-piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15 (d, J=3.0 Hz, 1H), 8.61 (br. s., 1H), 8.31(d, J=8.3 Hz, 1H), 8.36 (d, J=7.3 Hz, 1H), 8.05 (d, J=8.1 Hz, 1H),7.55-7.66 (m, 2H), 7.23 (t, J=7.1 Hz, 1H), 7.18 (d, J=8.3 Hz, 2H),7.02-7.12 (m, 4H), 4.52 (br. s., 1H), 3.51 (br. s., 2H), 3.22 (br. s.,1H), 2.65 (br. s., 1H), 2.14-2.29 (m, 1H), 2.09 (br. s., 1H), 1.79 (br.s., 1H). LC-MS: m/z 523.6 (M+H)⁺

Compound 113 General Procedure 2, Step CN-[4-[4-[2-(difluoromethyl)phenyl]-4-hydroxy-piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.02-9.07 (m, 2H), 8.51 (d, J=7.3 Hz, 1H), 8.38(d, J=8.3 Hz, 1H), 7.89 (t, J=7.9 Hz, 1H), 7.76 (s, 1H), 7.50-7.54 (m,1H), 7.39 (dd, J=7.5, 1.3 Hz, 1H), 7.29-7.32 (m, 1H), 7.22-7.28 (m, 2H),7.16 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.60 (br. s., 1H), 3.61 (br. s.,1H), 3.55 (br. s., 1H), 3.31 (d, J=11.3 Hz, 1H), 2.35 (d, J=7.5 Hz, 1H),2.20 (d, J=14.8 Hz, 1H), 2.01-2.12 (m, 2H), 1.97 (br. s., 2H). LC-MS:m/z 537.6 (M+H)⁺

Compound 266 General Procedure 2, Step CN-(4-(4-(2-cyanophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.2, 1.7 Hz, 1H), 8.39 (dd, J=7.3,1.3 Hz, 1H), 8.33 (dd, J=8.3, 1.6 Hz, 1H), 8.07 (dd, J=8.2, 1.2 Hz, 1H),7.92 (d, J=7.5 Hz, 1H), 7.71 (s, 1H), 7.54-7.67 (m, 3H), 7.38 (d, J=7.5Hz, 1H), 7.26 (d, J=8.9 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 4.66-4.84 (m,1H), 3.70-3.90 (m, 1H), 3.46-3.64 (m, 1H), 3.21-3.39 (m, 1H), 2.23 (s,2H), 1.71-1.88 (m, 2H). LC-MS: m/z 514.7 (M+H)⁺

Compound 255 General Procedure 2, Step CN-[4-[4-(4-cyanophenyl)-4-hydroxy-piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.42 (br. s., 1H), 9.29 (d, J=4.3 Hz, 1H), 8.50(d, J=8.1 Hz, 2H), 8.14 (d, J=8.1 Hz, 1H), 7.68-7.81 (m, 4H), 7.60 (d,J=7.5 Hz, 1H), 7.50 (t, J=7.8 Hz, 1H), 7.18-7.26 (m, 4H), 4.64 (t,J=17.2 Hz, 1H), 3.53-3.81 (m, 1H), 3.51 (s, 1H), 3.32 (s, 1H), 2.07 (br.s., 2H), 2.00 (br. s. 2H). LC-MS: m/z 512.6 (M+H)⁺

Compound 166 General Procedure 2, Step CN-(4-(4-(2-chloro-5-fluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)naphthalene-1-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.18 (d, J=3.0 Hz, 1H), 8.61 (br. s., 1H),8.30-8.42 (m, 2H), 8.07 (d, J=8.3 Hz, 1H), 7.58-7.68 (m, 2H), 7.49 (dd,J=7.0, 2.7 Hz, 1H), 7.30-7.37 (m, 1H), 7.19-7.26 (m, 2H), 7.11 (d, J=8.3Hz, 2H), 6.95-7.04 (m, 1H), 4.61 (br. s., 1H), 3.60 (br. s., 1H), 3.50(br. s., 1H), 3.23 (br. s., 1H), 2.16-2.31 (m, 1H), 2.09 (br. s., 1H),1.82 (br. s., 2H). LC-MS: m/z 541.1 (M+H)⁺

Compound 190 General Procedure 2, Step CN-[4-[4-(2-chloro-4-methyl-phenyl)-4-hydroxy-piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.79 (br. s., 1H), 1.94 (br. s., 1H), 2.05 (br.s., 1H), 2.13 (br. s., 1H), 2.32 (s, 3H), 2.98 (br. s., 1H), 3.27 (br.s., 1H), 3.56 (br. s., 2H), 4.58 (br. s., 1H), 7.07-7.11 (m, 3H),7.18-7.22 (m, 3H), 7.37 (d, J=8.03 Hz, 1H), 7.59-7.66 (m, 2H), 8.06 (dd,J=8.16, 1.13 Hz, 1H) 8.32 (dd, J=8.28, 1.51 Hz, 1H), 8.38 (dd, J=7.28,1.25 Hz, 1H), 8.60 (br. s., 1H), 9.17 (dd, J=4.27, 1.51 Hz, 1H). LC-MS:m/z 537.0 (M+H)⁺

Compound 111 General Procedure 2, Step CN-[4-[4-(2-chloro-4-fluoro-phenyl)-4-hydroxy-piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.57-1.76 (m, 4H), 2.04 (br. s., 1H), 2.13 (br.s., 1H), 3.57 (br. s., 2H), 4.57 (br. s., 1H), 6.97-7.04 (m, 1H), 7.10(d, J=8.06 Hz, 2H), 7.19-7.23 (m, 4H), 7.59-7.67 (m, 2H), 8.06 (d,J=8.06 Hz, 1H), 8.32 (d, J=8.33 Hz, 1H), 8.39 (d, J=7.52 Hz, 1H), 8.59(br. s., 1H), 9.17 (d, J=4.03 Hz, 1H). LC-MS: m/z 540.6 (M+H)⁺

Compound 123 General Procedure 2, Step CN-[4-[4-(2-chloro-3-fluoro-phenyl)-4-hydroxy-piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.70-1.90 (m, 4H), 3.28 (br. s., 1H), 3.51 (s,2H), 3.60 (br. s., 1H), 4.61 (br. s., 1H), 7.09-7.15 (m, 3H), 7.22 (d,J=8.33 Hz, 2H), 7.34-7.44 (m, 3H), 7.59-7.70 (m, 2H), 8.08 (d, J=8.33Hz, 1H), 8.36 (d, J=8.06 Hz, 1H), 8.41 (d, J=7.25 Hz, 1H), 8.77 (br. s.,1H), 9.20 (d, J=3.76 Hz, 1H). LC-MS: m/z 540.6 (M+H)⁺

Compound 182 General Procedure 2, Step CN-(4-(4-hydroxy-4-(3-(methylsulfonyl)phenyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.18 (dd, J=4.3, 1.3 Hz, 1H), 8.63 (br. s.,1H), 8.37 (dd, J=10.6, 1.2 Hz, 1H), 8.32-8.43 (m, 1H), 8.07 (dd, J=8.3,1.1 Hz, 1H), 7.89-7.96 (m, 2H), 7.57-7.74 (m, 5H), 7.14-7.19 (m, J=8.6Hz, 2H), 7.06-7.12 (m, J=8.6 Hz, 2H), 4.36 (br. s., 1H), 3.87 (br. s.,1H), 3.37-3.57 (m, 2H), 3.24-3.33 (m, 2H), 3.20 (br. s., 1H), 1.79 (br.s., 2H), 1.64 (br. s., 2H). LC-MS: m/z 566.7 (M+H)⁺

Compound 192 General Procedure 2, Step CN-[4-[4-hydroxy-4-(2-methylsulfonylphenyl)piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.95 (d, J=12.89 Hz, 3H), 1.99-2.11 (m, 2H),3.27 (br. s., 3H), 3.48 (br. s., 2H), 3.87 (br. s., 1H), 4.38 (br. s.,1H), 7.10 (m, J=8.60 Hz, 2H), 7.17 (m, J=8.60 Hz, 2H), 7.61-7.65 (m,3H), 7.69-7.74 (m, 1H), 7.93 (d, J=8.60 Hz, 2H), 8.07 (d, J=8.33 Hz,1H), 8.34 (d, J=8.33 Hz, 1H), 8.39 (d, J=7.25 Hz, 1H), 8.64 (br. s.,1H), 9.18 (d, J=3.49 Hz, 1H). LC-MS: m/z 566.7 (M+H)⁺

Compound 228 General Procedure 2, Step CN-[4-[4-hydroxy-4-(2-hydroxyphenyl)piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.94-2.09 (m, 4H), 2.21-2.27 (m, 1H), 2.50 (br.s., 1H), 3.30 (br. s., 1H), 3.50 (br. s., 1H), 3.62 (br. s., 1H), 4.63(br. s., 1H), 6.89 (t, J=8.06 Hz, 2H), 7.05-7.12 (m, 3H), 7.17-7.24 (m,3H), 7.60-7.67 (m, 2H), 8.07 (d, J=8.06 Hz, 1H), 8.32 (d, J=6.72 Hz,1H), 8.39 (d, J=7.25 Hz, 1H), 8.59 (br. s., 1H), 9.17 (d, J=5.91 Hz,1H). LC-MS: m/z 504.6 (M+H)⁺

Compound 156N-(4-(4-hydroxy-4-phenylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ: 9.05 (1H), 8.5 (m, 1H), 8.4 (m, 1H), 8.2 (m, 1H),7.7 (m, 2H), 7.4 (m, 2H), 7.4-7.05 (m, 7H), 4.2 (br, 2H), 3.2 (br, 2H),1.85 (br, 2H), 1.6 (br, 2H). LC-MS: m/z 488.6 (M+H)⁺

Compound 103N-(4-(4-hydroxy-4-(o-tolyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CD₃OD) δ: 9.1 (1H), 8.4 (m, 2H), 8.2 (m, 1H), 7.6 (m, 2H), 7.4(m, 1H), 7.2-7.05 (m, 7H), 4.4 (br, 1H), 3.5 (br, 2H), 2.5 (s, 3H),2.2-1.8 (m, 4H), 1.4 (br, 2H). LC-MS: m/z 502.6 (M+H)⁺

Compound 247 General Procedure 2, Step CN-[4-[4-(2-fluoropyridin-4-yl)-4-hydroxy-piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 2.08 (br. s., 1H), 2.14-2.37 (m, 2H), 2.75 (br.s., 1H), 3.22 (br. s., 1H), 3.49 (br. s., 2H), 3.56 (br. s., 1H), 4.55(br. s., 1H), 7.09 (d, J=8.60 Hz, 2H), 7.19 (d, J=8.60 Hz, 3H),7.56-7.66 (m, 2H), 7.94 (t, J=8.19 Hz, 1H), 8.05 (d, J=8.06 Hz, 1H),8.12 (d, J=4.57 Hz, 1H), 8.31 (d, J=8.33 Hz, 1H), 8.37 (d, J=7.25 Hz,1H), 8.62 (br. s., 1H), 9.16 (d, J=5.91 Hz, 1H). LC-MS: m/z 507.6 (M+H)⁺

Compound 265 General Procedure 2, Step CN-[4-[4-hydroxy-4-(6-methylpyridin-2-yl)piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.70 (br. s., 2H), 1.80 (br. s., 2H), 2.02 (br.s., 1H), 2.56 (s, 3H), 3.29 (br. s., 1H), 3.63 (br. s., 2H), 4.65 (br.s., 1H), 7.07-7.12 (m, 4H), 7.24 (d, J=8.60 Hz, 2H), 7.58-7.66 (m, 3H),8.05 (d, J=8.33 Hz, 1H), 8.31 (d, J=6.72 Hz, 1H), 8.38 (d, J=7.25 Hz,1H), 8.58 (br. s., 1H), 9.16 (d, J=5.91 Hz, 1H). LC-MS: m/z 503.6 (M+H)⁺

Compound 174 General Procedure 2, Step CN-[4-[4-hydroxy-4-[6-(trifluoromethyl)pyridin-2-yl]piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (dd, J=4.3, 1.6 Hz, 1H), 8.63 (br. s.,1H), 8.37 (dd, J=7.3, 1.3 Hz, 1H), 8.31 (dd, J=8.3, 1.6 Hz, 1H),8.02-8.08 (m, 1H), 7.92 (t, J=7.9 Hz, 1H), 7.55-7.66 (m, 4H), 7.20-7.25(m, J=8.6 Hz, 2H), 7.07-7.13 (m, J=8.3 Hz, 2H), 4.50-4.71 (m, 2H),3.60-3.71 (m, 1H), 3.50-3.60 (m, 1H), 1.80-1.97 (m, 2H), 1.74 (br. s.,2H). LC-MS: m/z 556.6 (M+H)⁺

Compound 211 General Procedure 2, Step CN-(4-(4-hydroxy-4-(2-methoxypyridin-3-yl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.12-9.19 (m, 1H), 8.61 (br. s., 1H), 8.37 (dd,J=7.3, 1.2 Hz, 1H), 8.30 (dd, J=8.4, 1.3 Hz, 1H), 8.09 (dd, J=5.0, 1.5Hz, 1H), 8.02-8.07 (m, 1H), 7.56-7.66 (m, 2H), 7.50 (dd, J=7.3, 1.8 Hz,1H), 7.19 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.5 Hz, 2H), 6.91 (dd, J=7.3,5.0 Hz, 1H), 4.57 (br. s., 1H), 4.02 (s, 3H), 3.89 (br. s., 1H), 3.56(br. s., 2H), 3.29 (br. s., 1H), 2.05-1.89 (m, 4H). LC-MS: m/z 519.6(M+H)⁺

Compound 129 General Procedure 2, Step CN-(4-(4-(6-fluoro-2-methylpyridin-3-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (dd, J=4.3, 1.6 Hz, 1H), 8.60 (br. s.,1H), 8.33 (dd, J=19.9, 1.3 Hz, 1H), 8.35 (dd, J=18.9, 1.5 Hz, 1H),8.02-8.10 (m, 1H), 7.70 (t, J=8.2 Hz, 1H), 7.56-7.66 (m, 2H), 7.17 (d,J=8.3 Hz, 2H), 7.08 (d, J=8.3 Hz, 2H), 6.68 (dd, J=8.6, 3.5 Hz, 1H),4.55 (br. s., 1H), 3.56 (br. s., 2H), 3.28 (br. s., 1H), 2.70 (s, 3H),1.92-2.08 (m, 4H). LC-MS: m/z 519.6 (M+H)⁺

Compound 171 General Procedure 2, Step CN-(4-(4-(5-fluoro-6-methylpyridin-2-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15 (dd, J=4.3, 1.9 Hz, 1H), 8.64 (br. s.,1H), 8.36 (dd, J=7.4, 1.2 Hz, 1H), 8.31 (dd, J=8.3, 1.6 Hz, 1H), 8.20(d, J=5.1 Hz, 1H), 8.05 (dd, J=8.2, 1.2 Hz, 1H), 7.55-7.67 (m, 2H),7.26-7.32 (m, 1H), 7.18 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.6 Hz, 2H), 4.53(br. s., 1H), 3.53 (br. s., 2H), 3.19 (br. s., 2H), 2.50 (d, J=3.5 Hz,3H), 2.04-2.23 (m, 2H), 1.61-1.73 (m, 2H). LC-MS: m/z 519.6 (M+H)⁺

Compound 148 General Procedure 2, Step CN-(4-(4-(3-fluoropyridin-2-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.3, 1.6 Hz, 1H), 8.60 (br. s.,1H), 8.41-8.46 (m, 2H), 8.39 (dd, J=7.3, 1.5 Hz, 1H), 8.33 (dd, J=8.4,1.6 Hz, 1H), 8.07 (dd, J=8.2, 1.2 Hz, 1H), 7.58-7.68 (m, 2H), 7.51 (dd,J=6.7, 5.3 Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 4.63(br. s., 1H), 3.60-3.23 (m, 3H), 2.32-1.86 (br. m., 4H). LC-MS: m/z507.5 (M+H)⁺

Compound 166N-(4-(4-(2-chloro-5-fluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)naphthalene-1-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.18 (d, J=3.0 Hz, 1H), 8.61 (br. s., 1H),8.30-8.42 (m, 2H), 8.07 (d, J=8.3 Hz, 1H), 7.58-7.68 (m, 2H), 7.49 (dd,J=7.0, 2.7 Hz, 1H), 7.30-7.37 (m, 1H), 7.19-7.26 (m, 2H), 7.11 (d, J=8.3Hz, 2H), 6.95-7.04 (m, 1H), 4.61 (br. s., 1H), 3.60 (br. s., 1H), 3.50(br. s., 1H), 3.23 (br. s., 1H), 2.16-2.31 (m, 1H), 2.09 (br. s., 1H),1.82 (br. s., 2H). LC-MS: m/z 541.0 (M+H)⁺

Compound 133 General Procedure 2, Step CN-(4-(4-(6-bromo-5-fluoropyridin-2-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.4, 1.8 Hz, 1H), 8.66 (br. s.,1H), 8.28-8.43 (m, 2H), 8.13 (d, J=5.0 Hz, 1H), 8.07 (dd, J=8.2, 1.2 Hz,1H), 7.57-7.70 (m, 2H), 7.44 (t, J=5.3 Hz, 1H), 7.19 (d, J=8.5 Hz, 2H),7.10 (d, J=8.5 Hz, 2H), 4.55 (br. s., 1H), 3.18-3.56 (m, 3H), 2.04-2.34(m, 2H), 1.63-1.65 (m, 2H). LC-MS: m/z 586.4 (M+H)⁺

Compound 147 General Procedure 2, Step CN-(4-(4-hydroxy-4-(2-methylpyridin-3-yl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.13 (dd, J=1.6, 4.3 Hz, 1H), 8.66 (br. s.,1H), 8.38-8.26 (m, 2H), 8.22 (d, J=4.7 Hz, 1H), 8.04 (dd, J=1.2, 8.2 Hz,1H), 7.66-7.51 (m, 3H), 7.18-7.10 (m, 2H), 7.10-6.97 (m, 3H), 4.47 (br.s., 1H), 3.53 (br. s., 1H), 3.47-3.32 (m, 1H), 3.26 (br. s., 1H), 2.70(s, 3H), 2.09-1.71 (m, 5H). LC-MS: m/z 503.6 (M+H)⁺

Compound 164 General Procedure 2, Step CN-(4-(4-hydroxy-4-(3-(trifluoromethyl)pyridin-2-yl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.20 (dd, J=4.3, 1.6 Hz, 1H), 8.75 (d, J=3.5Hz, 1H), 8.71 (s, 1H), 8.45-8.38 (m, 1H), 8.35 (d, J=8.4 Hz, 1H), 8.12(d, J=6.9 Hz, 1H), 8.08 (dd, J=8.2, 1.3 Hz, 1H), 7.71-7.59 (m, 2H), 7.43(dd, J=7.8, 4.9 Hz, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H),4.64 (s, 1H), 3.61 (s, 2H), 3.30 (s, 1H), 2.37 (s, 2H), 1.68 (d, J=11.9Hz, 3H). LC-MS: m/z 577.7 (M+H)⁺

Compound 191 General Procedure 2, Step CN-(4-(4-(3-chloropyridin-2-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.19 (dd, J=4.3, 1.7 Hz, 1H), 8.68 (s, 1H),8.50 (dd, J=4.6, 1.3 Hz, 1H), 8.40 (dd, J=7.3, 1.3 Hz, 1H), 8.35 (dd,J=8.3, 1.7 Hz, 1H), 8.08 (dd, J=8.2, 1.3 Hz, 1H), 7.78 (dd, J=8.0, 1.3Hz, 1H), 7.65 (ddd, J=13.7, 7.9, 4.4 Hz, 2H), 7.32-7.29 (m, 1H),7.28-7.21 (m, 2H), 7.18-7.09 (m, 2H), 4.68 (d, J=12.4 Hz, 1H), 3.60 (d,J=24.5 Hz, 2H), 3.31 (t, J=13.6 Hz, 1H), 2.75 (d, J=49.9 Hz, 2H), 1.52(d, J=9.9 Hz, 2H). LC-MS: m/z 523.6 (M+H)⁺

Compound 153 General Procedure 2, Step CN-(4-(4-hydroxy-4-(3-methylpyridin-2-yl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.18 (dd, J=4.3, 1.7 Hz, 1H), 8.56 (s, 1H),8.43-8.36 (m, 2H), 8.33 (dd, J=8.4, 1.8 Hz, 1H), 8.07 (dd, J=8.3, 1.3Hz, 1H), 7.69-7.59 (m, 2H), 7.53 (d, J=7.1 Hz, 1H), 7.26-7.18 (m, 3H),7.14-7.08 (m, 2H), 6.71 (s, 1H), 4.65 (s, 1H), 3.64 (s, 2H), 3.35 (s,1H), 2.51 (s, 3H), 2.39 (s, 1H), 2.24 (dd, J=10.2, 4.5 Hz, 1H), 1.56 (m,2H). LC-MS: m/z 503.6 (M+H)⁺

Compound 159 General Procedure 2, Step CN-(4-(4-hydroxy-4-(2-(trifluoromethyl)pyridin-3-yl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15 (dd, J=1.3, 4.3 Hz, 1H), 8.62 (d, J=4.4Hz, 1H), 8.42-8.26 (m, 2H), 8.11-7.92 (m, 2H), 7.69-7.55 (m, 2H), 7.47(dd, J=4.4, 8.2 Hz, 1H), 7.22-7.06 (m, 4H), 3.61-3.40 (m, 6H), 3.40-3.17(m, 2H), 2.07 (br. s., 1H), 2.04-1.74 (m, 5H). LC-MS: m/z 557.6 (M+H)⁺

Compound 217 General Procedure 2, Step CN-(4-(4-(2-fluoropyridin-3-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=1.8, 4.4 Hz, 1H), 8.64 (br. s.,1H), 8.42-8.27 (m, 2H), 8.13 (td, J=1.6, 4.7 Hz, 1H), 8.06 (dd, J=1.3,8.4 Hz, 1H), 7.94 (ddd, J=1.9, 7.7, 10.1 Hz, 1H), 7.69-7.55 (m, 2H),7.26-7.16 (m, 3H), 7.14-7.05 (m, 2H), 4.58 (br. s., 1H), 3.67-3.38 (m,2H), 3.23 (br. s., 1H), 2.22-2.09 (br. s., 5H). LC-MS: m/z 507.5 (M+H)⁺

Compound 206N-(4-(4-hydroxy-4-(pyridin-4-yl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.19-9.14 (m, 1H), 8.62 (s, 2H), 8.39 (d, J=7.3Hz, 1H), 8.32 (d, J=8.3 Hz, 1H), 8.07 (d, J=3.9 Hz, 2H), 7.68-7.58 (m,2H), 7.44 (s, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 4.66(s, 1H), 3.68 (s, 1H), 3.49 (s, 1H), 3.28 (s, 1H), 1.87-1.64 (m, 4H).LC-MS: m/z 489.4 (M+H)⁺

Compound 161N-(4-(4-(3-chloropyridin-4-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.2, 1.5 Hz, 1H), 8.62 (s, 1H),8.55 (s, 1H), 8.50 (s, 1H), 8.38 (dd, J=7.3, 1.1 Hz, 1H), 8.32 (dd,J=8.3, 1.5 Hz, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.68-7.58 (m, 2H), 7.54 (d,J=4.9 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 4.61 (s,1H), 3.65 (d, J=19.1 Hz, 1H), 3.25 (s, 2H), 2.83 (s, 1H), 2.41 (d,J=57.6 Hz, 2H), 1.84 (s, 1H). LC-MS: m/z 523.6 (M+H)⁺

Compound 377 General Procedure 2, Step C(4-hydroxy-4-(isothiazol-4-yl)piperidin-1-yl)(4-((quinolin-8-ylsulfonyl)methyl)phenyl)methanone

¹H NMR (CHLOROFORM-d) δ: 9.15 (d, J=2.7 Hz, 1H), 8.39-8.46 (m, 2H), 8.38(s, 1H), 8.18 (d, J=8.3 Hz, 1H), 7.62-7.71 (m, 2H), 7.17-7.25 (m, 5H),4.45 (br. s., 1H), 3.49 (br. s., 2H), 2.00 (br. s., 3H), 1.81 (br. s.,1H), 1.31 (br. s., 1H). LC-MS: m/z 495.6 (M+H)⁺

General Procedure 3

Step A:

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1 eq.) in THFwas added dropwise the corresponding RMgBr solution in THF (4 eq.) via asyringe at −30° C. After the addition, the resulting mixture was stirredat −30° C. under N₂ for 2 h, then allowed to warm to r.t. The reactionmixture was quenched by satd. NH₄Cl solution, and the resulting mixturewas extracted with EtOAc (50 mL, 30 mL). The combined organic phase waswashed with brine, dried over anhydrous Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography (PE/EtOAc) togive the desired compound 3B.

Step B:

To a solution of compound 3B (1 eq.) in DCM, was added TFA (10 eq.), thereaction mixture was stirred at room temperature for about 2 hours, whenLCMS detected no s.m. The reaction mixture was concentrated to affordthe desired product 3C. The crude product was used for the next stepdirectly without further purification.

Step C:

To a round-bottomed flask was added compound 3C (1 eq.), DMF (5 mL),DIPEA (3.0 eq.), HBTU (1.2 eq.), and 1A (1 eq.) sequentially. Thereaction mixture was stirred at room temperature overnight or until TLCindicated that s.m. was consumed. The mixture was diluted with brine,extracted with ethyl acetate, the organic layer was dried with anhydrousNa₂SO₄, filtered, and filtrate was concentrated. The desired product waspurified by a standard method.

Compound 214 General Procedure 3, Step CN-(4-(4-hydroxy-4-isopropylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.23 (s, 1H), 8.96 (s, 1H), 8.48-8.34 (m, 2H),8.10 (d, J=8.1 Hz, 1H), 7.76-7.61 (m, 2H), 7.18 (d, J=8.4 Hz, 2H), 7.13(d, J=8.5 Hz, 2H), 4.48 (s, 1H), 3.50 (s, 1H), 3.33 (s, 1H), 3.11 (s,1H), 1.65-1.56 (m, 1H), 1.41 (d, J=53.9 Hz, 4H), 0.92 (d, J=6.9 Hz, 6H).LC-MS: m/z 454.6 (M+H)⁺

Compound 260 General Procedure 3, Step CN-(4-(4-cyclopropyl-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.3, 1.7 Hz, 1H), 8.58 (s, 1H),8.39 (dd, J=7.3, 1.3 Hz, 1H), 8.33 (dd, J=8.4, 1.7 Hz, 1H), 8.07 (dd,J=8.2, 1.3 Hz, 1H), 7.69-7.59 (m, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.10 (d,J=8.6 Hz, 2H), 5.28 (t, J=7.0 Hz, 1H), 3.65 (t, J=6.4 Hz, 4H), 3.32 (s,2H), 2.40-2.22 (m, 4H), 2.14 (dd, J=23.1, 12.0 Hz, 2H). LC-MS: m/z 452.6(M+H)⁺

Compound 183 General Procedure 3, Step CN-(4-(4-hydroxy-4-propylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.3, 1.7 Hz, 1H), 8.55 (s, 1H),8.38 (dd, J=7.3, 1.3 Hz, 1H), 8.32 (dd, J=8.4, 1.7 Hz, 1H), 8.06 (dd,J=8.2, 1.3 Hz, 1H), 7.68-7.58 (m, 2H), 7.17 (d, J=8.6 Hz, 2H), 7.08 (d,J=8.6 Hz, 2H), 4.34 (s, 1H), 3.52-3.10 (m, 3H), 1.46 (dd, J=10.2, 4.6Hz, 4H), 1.33 (ddd, J=26.6, 11.0, 7.3 Hz, 4H), 0.95 (t, J=7.0 Hz, 3H).LC-MS: m/z 454.6 (M+H)⁺

Compound 140 General Procedure 3, Step CN-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.3, 1.7 Hz, 1H), 8.56 (s, 1H),8.38 (dd, J=7.3, 1.3 Hz, 1H), 8.32 (dd, J=8.4, 1.6 Hz, 1H), 8.06 (dd,J=8.2, 1.3 Hz, 1H), 7.68-7.58 (m, 2H), 7.17 (d, J=8.5 Hz, 2H), 7.09 (d,J=8.6 Hz, 2H), 4.34 (s, 1H), 3.43 (s, 1H), 3.35 (s, 1H), 3.20 (s, 1H),1.83 (tt, J=13.0, 6.5 Hz, 1H), 1.49 (s, 2H), 1.41 (d, J=6.0 Hz, 2H),1.31 (d, J=23.9 Hz, 2H), 0.98 (d, J=6.6 Hz, 6H). LC-MS: m/z 468.6 (M+H)⁺

Compound 195 General Procedure 3, Step CN-(4-(4-(tert-butyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.19 (dd, J=4.3, 1.5 Hz, 1H), 8.71 (s, 1H),8.40 (dd, J=7.3, 1.3 Hz, 1H), 8.35 (dd, J=8.3, 1.4 Hz, 1H), 8.08 (dd,J=8.2, 1.2 Hz, 1H), 7.70-7.60 (m, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.10 (d,J=8.5 Hz, 2H), 4.52 (s, 1H), 3.54 (s, 1H), 3.32 (s, 1H), 3.04 (s, 1H),1.71 (s, 4H), 0.93 (s, 9H). LC-MS: m/z 468.6 (M+H)⁺

Compound 124 General Procedure 3, Step CN-(4-(4-(cyclobutylmethyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.2, 1.5 Hz, 1H), 8.56 (s, 1H),8.38 (dd, J=7.3, 1.3 Hz, 1H), 8.32 (dd, J=8.3, 1.5 Hz, 1H), 8.06 (dd,J=8.2, 1.2 Hz, 1H), 7.68-7.58 (m, 2H), 7.17 (d, J=8.5 Hz, 2H), 7.08 (d,J=8.5 Hz, 2H), 4.33 (s, 1H), 3.51-3.08 (m, 3H), 2.57-2.43 (m, 1H),2.14-2.01 (m, 2H), 1.91 (dd, J=18.4, 9.5 Hz, 1H), 1.79 (dd, J=10.5, 8.5Hz, 1H), 1.76-1.64 (m, 4H), 1.61 (s, 2H), 1.43-1.35 (m, 2H). LC-MS: m/z480.6 (M+H)⁺

General Procedure 4

Step A:

To a solution of diethyl ether (freshly distilled fromsodium/benzophenone) containing a catalytic amount of 1,2-dibromoethanewas added magnesium turnings (6.6 eq.) under argon and the resultingmixture was stirred at room temperature for 30 min. A solution ofsubstituted benzyl bromide/chloride (5 eq.) in dry diethyl ether wasthen added slowly to the reaction mixture over a period of 2 h andstirring was continued at room temperature for additional 2 h. Thereaction mixture was then cooled to 0° C., when compound 4A (1 eq.)taken in a solution of dry diethyl ether was slowly added to thereaction mixture under argon atmosphere. The resulting reaction mixturewas allowed to stir at room temperature for another 4 hrs. The progressof the reaction was monitored by TLC. Upon completion of the reaction,the mixture was quenched with satd. NH₄CI solution, and extracted withEtOAc. The combined organic layers were washed with water, dried overNa₂SO₄ and concentrated under reduced pressure to give the crudeproduct. The crude product was then purified by column chromatographyusing silica gel (100-200 mesh) and 20% EtOAc in hexane to afforddesired compound 4B.

Step B:

Compound 4B (1 eq.) was dissolved in DCM and cooled to 0° C., when TFA(10 eq.) was added at 0° C. The reaction mixture was allowed to warm tor.t. and stirred for 3-4 hrs at r.t. until LCMS and TLC confirmedcompletion of reaction. The reaction mixture was concentrated to get thecrude product which was triturated 3 to 4 times with DCM and n-pentaneto afford compound 4C.

Step C:

To a solution of compound 4C (1.2 eq.) in DMF, 1A (1 eq.) was addedfollowed by addition of DIPEA (2 eq.), HATU (1.2 eq.) and DMAP (0.1 eq.)at room temperature under nitrogen atmosphere. The reaction mixture wasallowed to stir at room temperature for 16 hrs. The progress of thereaction was monitored by TLC and upon completion of reaction the crudemixture was diluted with EtOAc and washed sequentially with water andsaturated sodium bicarbonate solution. The resulting organic layer wasthen separated, dried over Na₂SO₄ and concentrated under reducedpressure to give the crude product which was purified by a standardmethod to afford desired compound 4D.

Compound 110 General Procedure 4, Step CN-(4-(4-(2-fluorobenzyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14 (s, 1H), 8.51 (bs, 1H), 8.32 (dd, 2H,J=6.8 Hz & J=7.6 Hz), 8.03 (d, 1H, J=8 Hz), 7.61-7.57 (m, 2H), 7.18-7.05(m, 8H), 4.36 (bs, 1H), 3.44 (m, 1H), 3.27 (m, 1H), 3.13 (m, 1H),2.96-2.88 (m, 2H), 2.80 (s, 2H), 1.33-1.25 (m, 3H). LC-MS: m/z 520.2(M+H)⁺

Compound 105 General Procedure 4, Step CN-(4-(4-(3-fluorobenzyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ: 10.40 (s, 1H), 9.13-9.12 (m, 1H), 8.45 (dd, 2H,J=8.4 Hz & J=7.2 Hz), 8.27 (d, 1H, J=8 Hz), 7.74-7.69 (m, 2H), 7.29-7.25(m, 1H), 7.18-6.98 (m, 7H), 4.49 (s, 1H), 4.06 (m, 1H), 3.62-3.61 (m,1H), 3.18-3.12 (m, 2H), 2.68 (s, 2H), 1.38-1.33 (m, 4H). LC-MS: m/z520.2 (M+H)⁺

Compound 118 General Procedure 4, Step CN-(4-(4-hydroxy-4-(3-methylbenzyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15-9.13 (m, 1H), 8.52 (bs, 1H), 8.36-8.28 (m,2H), 8.03 (d, 1H, J=7.6 Hz), 7.63-7.57 (m, 2H), 7.22-7.05 (m, 5H),6.99-6.93 (m, 2H), 4.37 (bs, 1H), 3.90-3.45 (m, 2H), 3.27-2.98 (m, 2H),2.70 (s, 2H), 2.33 (s, 2H), 1.51-132 (m, 4H). LC-MS: m/z 516.2 (M+H)⁺

Compound 108 General Procedure 4, Step CN-(4-(4-hydroxy-4-(2-methylbenzyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14-9.13 (m, 1H), 8.52 (bs, 1H), 8.36-8.28 (m,2H), 8.03 (d, 1H, J=8.4 Hz), 7.63-7.57 (m, 2H), 7.18-7.05 (m, 8H),4.35-4.48 (m, 1H), 3.60-2.95 (m, 3H), 2.80-2.79 (m, 3H), 2.33 (s, 3H),1.52-1.39 (m, 4H). LC-MS: m/z 516.2 (M+H)⁺

Compound 116 General Procedure 4, Step CN-(4-(4-hydroxy-4-(2-methoxybenzyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ: 9.15-9.14 (m, 1H), 8.51 (bs, 1H), 8.36-8.28 (dd, 2H,J=4.2 Hz & J=8 Hz), 8.03 (d, 1H, J=8 Hz), 7.63-7.57 (m, 2H), 7.24-6.98(m, 6H), 6.94-6.89 (m, 2H), 4.33 (bs, 1H), 3.83 (s, 3H), 3.41-3.12 (m,3H), 2.85-2.83 (m, 3H), 1.57-1.29 (m, 4H). LC-MS: m/z 532.6 (M+H)⁺

Compound 135 General Procedure 4, Step CN-(4-(4-hydroxy-4-(3-methoxybenzyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15-9.14 (m, 1H), 8.51 (s, 1H), 8.32 (dd, 2H,J=7.2 Hz & J=8 Hz), 8.03 (d, 1H, J=8 Hz), 7.63-7.57 (m, 2H), 7.23-7.05(m, 5H), 6.90-6.68 (m, 3H), 4.38 (m, 1H), 3.79 (s, 3H), 3.60-2.98 (m,4H), 2.71 (s, 2H), 1.54-1.40 (m, 4H). LC-MS: m/z 532.6 (M+H)⁺

Compound 152 General Procedure 4, Step CN-(4-(4-hydroxy-4-(3-(trifluoromethyl)benzyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14-9.13 (m, 1H), 8.53 (bs, 1H), 8.32 (dd, 2H,J=6.8 Hz, J=8.4 Hz), 8.03 (d, 1H, J=8 Hz), 7.63-7.50 (m, 3H), 7.45-7.33(m, 3H), 7.16-7.00 (m, 4H), 4.38 (m, 1H), 3.50-3.45 (m, 1H), 3.28-2.91(m, 2H), 2.90-2.79 (m, 3H), 1.58-1.33 (m, 4H). LC-MS: m/z 570.2 (M+H)⁺

General Procedure 5

Step A: 4-(2,2,2-trifluoroacetamido)benzoic acid (5B)

To a mixture of 4-aminobenzoic acid (44 g, 0.32 mmol) in TFA (300 mL)was added trifluoroacetic anhydride (100 mL) dropwise, keeping thetemperature below 10° C. After the addition, the mixture was stirred atroom temperature overnight. The mixture was then poured into crushedice, the precipitate that formed was filtered, and was dried in vacuoovernight to give the title compound (2, 72 g). ¹H NMR (DMSO-d₆) δ:11.52 (s, 1H), 7.93-8.07 (m, 2H), 7.76-7.86 (m, 2H). LC-MS: m/z 234.1(M+H)⁺

Step B

To a round-bottomed flask was added the corresponding compound 3 (21mmol, 1 eq.), DMF (50 mL), DIPEA (3.0 eq.), HBTU (1.2 eq.), andintermediate 2 (5 g, 21 mmol, 1 eq.) sequentially. The reaction mixturewas stirred at room temperature overnight or until TLC indicated thats.m. was consumed. The mixture was diluted with brine, extracted withethyl acetate, the organic layer was dried with anhydrous Na₂SO₄,filtered, and the filtrate was concentrated. The desired product waspurified by silica gel chromatography. 5C-1, LC-MS: m/z 427.8 (M+H)⁺;5C-2, LC-MS: m/z 373.4 (M+H)⁺; 5C-3, LC-MS: m/z 429.4 (M+H)⁺; 5C-4,LC-MS: m/z 407.4 (M+H)⁺

Step C

To a mixture of the corresponding compound 5C (1 eq.) in methanol, wasadded K₂CO₃ (2 eq.). The mixture was stirred at room temperatureovernight, when TLC indicated consumption of s.m. and product formation.The mixture was then concentrated in vacuo, partitioned between brineand EtOAc, the organic layer was separated and concentrated to give thecrude product. Further purification was done by a standard method.

1B: (4-aminophenyl)(4-(2-chlorophenyl)-4-hydroxypiperidin-1-yl)methanone

¹H NMR (CHLOROFORM-d) δ: 7.55 (dd, J=7.9, 1.7 Hz, 1H), 7.41 (dd, J=7.8,1.3 Hz, 1H), 7.29-7.34 (m, 3H), 7.23-7.28 (m, 1H), 6.66-6.71 (m, 2H),4.59 (br. s., 1H), 3.88 (br. s., 2H), 3.50 (br. s., 2H), 2.97 (br. s.,1H), 2.33 (br. s., 2H), 2.20-2.29 (m, 1H), 1.97-2.16 (m, 2H). LC-MS: m/z331.8 (M+H)⁺

1C: (4-aminophenyl)(4-hydroxy-4-isobutylpiperidin-1-yl)methanone

¹H NMR (CHLOROFORM-d) δ: 7.21-7.33 (m, 2H), 6.63-6.72 (m, 2H), 3.35 (br.s., 2H), 1.87 (dt, J=12.9, 6.4 Hz, 1H), 1.62 (br. s., 4H), 1.44 (d,J=5.9 Hz, 2H), 1.00 (d, J=6.7 Hz, 6H). LC-MS: m/z 277.4 (M+H)⁺

1D:(4-aminophenyl)(4-(2,3-difluorophenyl)-4-hydroxypiperidin-1-yl)methanone

LC-MS: m/z 333.3 (M+H)⁺

1E: (4-aminophenyl)(4-benzyl-4-hydroxypiperidin-1-yl)methanone

¹H NMR (DMSO-d₆) δ: 7.44 (d, 2H, J=8 Hz), 7.32-7.16 (m, 5H), 6.66 (d,2H, J=8.4 Hz), 4.80 (m, 2H), 4.37 (m, 2H), 2.29 (s, 2H). LC-MS: m/z311.4 (M+H)⁺

Step D

To a suspension of the 1B-1E (0.5 mmol) and sulfonyl chloride (80 mg,0.55 mmol) in 30 mL of anhydrous THF, was added pyridine (1.0 mmol) atroom temperature. The resulting mixture was heated and stirred at refluxfor 6 h. The reaction mixture was cooled to room temperature, thenextracted with EtOAc (100 mL×2). The combined organic phase was washedwith brine, dried over anhy. Na₂SO₄ and concentrated in vacuo. The titlecompound was obtained by a standard purification method.

Compound 155 General Procedure 5, Step DN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.10 (d,J=7.5 Hz, 1H), 7.94 (s, 1H), 7.54 (dd, J=15.3, 7.6 Hz, 2H), 7.40 (dd,J=7.6, 1.3 Hz, 1H), 7.32 (d, J=6.5 Hz, 1H), 7.27 (d, J=9.2 Hz, 1H), 7.24(d, J=8.2 Hz, 2H), 7.13 (d, J=7.9 Hz, 2H), 4.61 (s, 1H), 3.58 (s, 2H),3.32 (s, 1H), 2.42-1.96 (m, 4H). LC-MS: m/z 528.6 (M+H)⁺

Compound 179 General Procedure 5, Step DN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-5-fluoroquinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.72 (br. s., 2H), 1.96 (br. s., 1H), 2.18 (br.s., 1H), 2.33 (br. s., 1H), 2.96 (br. s., 1H), 3.28 (br. s., 1H), 3.57(br. s., 2H), 4.61 (br. s., 1H), 7.08 (d, J=8.60 Hz, 2H), 7.21 (d,J=8.33 Hz, 2H), 7.23-7.28 (m, 2H), 7.29-7.32 (m, 1H), 7.38 (dd, J=7.52,1.34 Hz, 1H), 7.51 (dd, J=7.66, 1.48 Hz, 1H), 7.70 (dd, J=8.33, 4.30 Hz,1H), 8.34-8.43 (m, 2H), 8.57 (dd, J=8.46, 1.48 Hz, 1H), 9.19-9.24 (m,1H). LC-MS: m/z 540.1 (M+H)⁺

Compound 259N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-2-fluoroquinoline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.22 (t, J=8.0 Hz, 1H), 8.98 (br. s., 1H), 8.21(d, J=8.0 Hz, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H), 7.53(d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.28-7.13 (m, 5H), 6.94 (d,J=8.0 Hz, 2H), 4.64 (br. s., 1H), 3.55 (br. s., 2H), 3.35 (br. s., 1H),3.17 (br. s., 1H), 2.42 (br. s., 1H), 2.21 (s, 1H), 2.08 (s, 1H), 1.95(s, 1H). LC-MS: m/z 541.1 (M+H)⁺

Compound 244 General Procedure 5, Step DN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[c]isothiazole-7-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.45 (s, 1H), 8.12 (d, J=6.2 Hz, 1H), 8.03 (d,J=8.6 Hz, 1H), 7.89 (s, 1H), 7.51 (dd, J=7.7, 1.5 Hz, 1H), 7.40 (dd,J=7.7, 1.5 Hz, 1H), 7.30-7.35 (m, 2H), 7.26 (dd, J=7.5, 1.6 Hz, 1H),7.22 (d, J=8.6 Hz, 2H), 7.11 (d, J=8.3 Hz, 2H), 4.59 (br. s., 1H), 3.57(br. s., 2H), 3.34 (br. s., 2H), 2.26 (br. s., 2H), 2.04 (br. s., 3H).LC-MS: m/z 529.1 (M+H)⁺

Compound 173 General Procedure 5, Step DN-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.10 (d,J=7.5 Hz, 1H), 7.93 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.3 Hz,2H), 7.11 (d, J=8.4 Hz, 2H), 3.28 (s, 2H), 1.83 (dt, J=12.8, 6.5 Hz,1H), 1.56 (s, 7H), 1.42 (d, J=6.0 Hz, 2H), 0.98 (d, J=6.6 Hz, 6H).LC-MS: m/z 474.6 (M+H)⁺

Compound 378 General Procedure 5, Step DN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-7-fluorobenzo[d]thiazole-4-sulfonamide

¹H NMR (DMSO-d₆) δ: 10.87 (s, 1H), 9.73 (s, 1H), 8.19 (dd, J=8.6, 5.1Hz, 1H), 7.80 (dd, J=7.9, 1.5 Hz, 1H), 7.57 (t, J=8.7 Hz, 1H), 7.32-7.40(m, 2H), 7.24-7.29 (m, 1H), 7.19-7.23 (m, J=8.6 Hz, 2H), 7.10-7.16 (m,J=8.6 Hz, 2H), 5.41 (s, 1H), 4.30 (br. s., 1H), 3.43 (br. s., 1H), 2.46(br. s., 2H). LC-MS: m/z 529.1 (M+H)⁺

Compound 203 General Procedure 5, Step D5-fluoro-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.22 (d, J=2.8 Hz, 1H), 8.58 (dd, J=8.5, 1.3Hz, 1H), 8.44-8.32 (m, 2H), 7.71 (dd, J=8.5, 4.3 Hz, 1H), 7.18 (d, J=8.3Hz, 2H), 7.08 (d, J=8.3 Hz, 2H), 4.33 (s, 1H), 3.31 (s, 3H), 1.83 (dt,J=12.8, 6.3 Hz, 1H), 1.57 (s, 4H), 1.41 (d, J=6.0 Hz, 2H), 0.98 (d,J=6.6 Hz, 6H). LC-MS: m/z 486.7 (M+H)⁺

Compound 240 General Procedure 5, Step D7-fluoro-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.32 (s, 1H), 8.12 (dd, J=8.3, 4.8 Hz, 1H),7.84 (s, 1H), 7.22-7.27 (m, 1H), 7.20 (d, J=8.6 Hz, 2H), 7.09 (d, J=8.6Hz, 2H), 4.25-4.46 (m, 1H), 3.42 (br. s., 2H), 3.20 (br. s., 1H), 1.83(dt, J=12.9, 6.4 Hz, 1H), 1.55-1.70 (m, 3H), 1.51 (br. s., 1H), 1.42 (d,J=6.2 Hz, 2H), 0.98 (d, J=6.4 Hz, 6H). LC-MS: m/z 492.6 (M+H)⁺

Compound 145 General Procedure 5, Step D2-amino-6-fluoro-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 8.09 (s, 1H), 7.59 (dd, J=8.2, 2.5 Hz, 1H),7.49 (dd, J=7.5, 2.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.5 Hz,2H), 5.98 (d, J=15.1 Hz, 2H), 4.37 (s, 1H), 3.43 (d, J=30.3 Hz, 2H),3.22 (s, 1H), 1.85 (dt, J=12.9, 6.4 Hz, 1H), 1.49 (d, J=28.9 Hz, 4H),1.43 (d, J=6.0 Hz, 2H), 0.99 (d, J=6.6 Hz, 6H). LC-MS: m/z 507.78 (M+H)⁺

Compound 379 General Procedure 5, Step DN-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d]oxazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 8.33 (s, 1H), 7.92 (d, J=7.7 Hz, 1H), 7.83 (d,J=8.2 Hz, 1H), 7.61 (s, 1H), 7.49 (t, J=8.0 Hz, 1H), 7.22 (d, J=8.4 Hz,2H), 7.15 (d, J=8.4 Hz, 2H), 4.35 (s, 1H), 3.40 (d, J=25.4 Hz, 2H), 3.21(s, 1H), 1.89-1.77 (m, 1H), 1.65 (s, 4H), 1.42 (d, J=6.0 Hz, 2H), 0.98(d, J=6.6 Hz, 6H). LC-MS: m/z 458.72 (M+H)⁺

Compound 380 General Procedure 5, Step D2-amino-3-hydroxy-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzenesulfonamide

¹H NMR (CHLOROFORM-d) δ: 10.54 (s, 1H), 9.95 (s, 1H), 7.24 (d, J=8.6 Hz,2H), 7.10-7.03 (m, 3H), 6.81 (dd, J=7.7, 1.2 Hz, 1H), 6.45 (t, J=8.0 Hz,1H), 5.47 (s, 2H), 4.18 (s, 1H), 4.08 (s, 1H), 3.33-2.95 (m, 3H), 1.80(dp, J=12.7, 6.4 Hz, 1H), 1.44 (d, J=48.4 Hz, 4H), 1.29 (d, J=5.7 Hz,2H), 0.90 (d, J=6.6 Hz, 6H). LC-MS: m/z 448.69 (M+H)⁺

Compound 381 General Procedure 5, Step DN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]oxazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 8.33 (s, 1H), 7.93 (d, J=7.7 Hz, 1H), 7.83 (d,J 8.2 Hz, 1H), 7.70 (s, 1H), 7.56-7.46 (m, 2H), 7.40 (dd, J=7.6, 1.3 Hz,1H), 7.35-7.30 (m, 1H), 7.26 (d, J=8.5 Hz, 3H), 7.17 (d, J=8.4 Hz, 2H),4.63 (s, 1H), 3.60 (s, 2H), 3.31 (s, 1H), 2.94 (s, 1H), 2.36 (s, 1H),2.20 (s, 1H), 2.10 (s, 1H), 1.99 (s, 1H). LC-MS: m/z 512.67 (M+H)⁺

Compound 382 General Procedure 5, Step D2-amino-N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-3-hydroxybenzenesulfonamide

¹H NMR (CHLOROFORM-d) δ: 10.57 (s, 1H), 9.94 (d, J=3.7 Hz, 1H), 7.81(dd, J=7.9, 1.6 Hz, 1H), 7.44-7.32 (m, 2H), 7.32-7.23 (m, 3H), 7.15-7.03(m, 3H), 6.81 (d, J=7.7 Hz, 1H), 6.45 (t, J=7.9 Hz, 1H), 5.48 (s, 2H),5.42 (s, 1H), 4.36 (s, 1H), 3.48 (s, 2H), 3.11 (s, 1H), 2.41 (s, 1H),1.53 (d, J=38.6 Hz, 3H). LC-MS: m/z 502.66 (M+H)⁺

Compound 383 General Procedure 5, Step DN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-2-methylbenzo[d]oxazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 7.83 (d, J=7.8 Hz, 1H), 7.78 (s, 1H), 7.68 (d,J=8.2 Hz, 1H), 7.53 (d, J=6.6 Hz, 1H), 7.37 (dd, J=13.5, 7.1 Hz, 2H),7.32-7.21 (m, 4H), 7.16 (d, J=8.4 Hz, 2H), 4.61 (s, 1H), 3.60 (s, 2H),3.31 (s, 1H), 3.04 (s, 1H), 2.76 (s, 3H), 2.38 (s, 1H), 2.19 (s, 1H),2.02 (d, J=45.1 Hz, 2H). LC-MS: m/z 526.70 (M+H)⁺

Compound 384 General Procedure 5, Step DN-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)-2-methylbenzo[d]oxazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 7.83 (dd, J=7.8, 0.7 Hz, 1H), 7.68 (d, J=8.1Hz, 1H), 7.59 (s, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.23 (d, J=8.5 Hz, 2H),7.14 (d, J=8.5 Hz, 2H), 4.35 (s, 1H), 3.39 (dd, J=73.0, 45.6 Hz, 3H),2.77 (s, 3H), 1.84 (dp, J=12.9, 6.5 Hz, 1H), 1.65 (s, 3H), 1.52 (s, 1H),1.42 (d, J=6.0 Hz, 2H), 0.99 (d, J=6.6 Hz, 6H). LC-MS: m/z 472.70 (M+H)⁺

Compound 385 General Procedure 5, Step D6-chloro-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)-2-(methylamino)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 7.98 (br. s., 1H), 7.78 (d, 1=1.9 Hz, 1H), 7.71(d, J=1.9 Hz, 1H), 7.26 (d, J=8.6 Hz, 2H), 7.10-7.14 (m, 2H), 3.44 (br.s., 1H), 3.22 (d, J=3.2 Hz, 3H), 1.82-1.87 (m, 1H), 1.64-1.66 (m, 2H),1.42-1.44 (m, 2H), 0.99 (d, J=6.7 Hz, 6H). LC-MS: m/z 538.1 (M+H)⁺

Compound 154 General Procedure 5, Step D2-amino-N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-6-fluorobenzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 8.01 (s, 1H), 7.59 (dd, J=8.2, 2.5 Hz, 1H),7.53 (dd, J=7.9, 1.8 Hz, 1H), 7.49 (dd, J=7.5, 2.6 Hz, 1H), 7.41 (dd,J=7.7, 1.5 Hz, 1H), 7.32 (dd, J=7.5, 1.5 Hz, 1H), 7.30 (d, J=3.8 Hz,2H), 7.25 (dd, J=7.5, 1.7 Hz, 1H), 7.15 (d, J=8.5 Hz, 2H), 5.83 (s, 2H),4.64 (s, 1H), 3.62 (s, 2H), 3.34 (s, 1H), 2.37 (s, 1H), 2.26-2.17 (m,1H), 2.08 (d, J=10.1 Hz, 1H), 2.03 (s, 1H). LC-MS: m/z 561.71 (M+H)⁺

Compound 173 General Procedure 5, Step DN-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.10 (d,J=7.5 Hz, 1H), 7.93 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.3 Hz,2H), 7.11 (d, J=8.4 Hz, 2H), 3.28 (s, 2H), 1.83 (dt, J=12.8, 6.5 Hz,1H), 1.56 (s, 7H), 1.42 (d, J=6.0 Hz, 2H), 0.98 (d, J=6.6 Hz, 6H).LC-MS: m/z 474.6 (M+H)⁺

Compound 203 General Procedure 5, Step D5-fluoro-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.22 (d, J=2.8 Hz, 1H), 8.58 (dd, J=8.5, 1.3Hz, 1H), 8.44-8.32 (m, 2H), 7.71 (dd, J=8.5, 4.3 Hz, 1H), 7.18 (d, J=8.3Hz, 2H), 7.08 (d, J=8.3 Hz, 2H), 4.33 (s, 1H), 3.31 (s, 3H), 1.83 (dt,J=12.8, 6.3 Hz, 1H), 1.57 (s, 4H), 1.41 (d, J=6.0 Hz, 2H), 0.98 (d,J=6.6 Hz, 6H). LC-MS: m/z 486.7 (M+H)⁺

Compound 227 General Procedure 5, Step DN-(4-(4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-5-fluoroquinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.24 (br. s., 1H), 8.59 (d, J=7.8 Hz, 1H), 8.47(br. s., 1H), 8.36-8.42 (m, 1H), 7.68-7.76 (m, 1H), 7.18-7.28 (m, 4H),7.10 (d, m, 4H), 4.58 (br. s., 1H), 3.52 (br. s., 2H), 3.25 (br. s.,1H), 1.99-2.29 (m, 4H). LC-MS: m/z 543.6 (M+H)⁺

Compound 205 General Procedure 5, Step DN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[c][1,2,5]thiadiazole-4-sulfonamide

¹H NMR (DMSO-d6) δ: 10.98 (bs, 1H), 8.33 (dd, 2H, J=8.8 Hz, J=6.8 Hz),7.86-7.81 (m, 1H), 7.25-7.12 (m, 7H), 7.07 (d, 2H, J=8.4 Hz), 4.42 (s,1H), 4.25-3.90 (m, 1H), 3.21-2.98 (m, 3H), 2.65 (s, 2H), 1.54-1.42 (m,4H). LC-MS: m/z 543.6 (M+H)⁺

Compound 106 General Procedure 5, Step DN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)phenyl)-2,3,4a,8a-tetrahydrobenzo[b][1,4]dioxine-5-sulfonamide

¹H NMR (DMSO-d₆) δ: 10.31 (s, 1H), 7.38-7.16 (m, 8H), 7.15-7.00 (m, 3H),6.90 (t, 1H, J=8 Hz), 4.44 (bs, 1H), 4.28 (d, 4H, J=8.4 Hz), 4.19-4.10(m, 1H), 3.51-3.25 (m, 3H), 2.68 (s, 2H), 1.61-1.30 (m, 4H). LC-MS: m/z511.6 (M+H)⁺

Compound 239 General Procedure 5, Step DN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)phenyl)-6-chlorocyclohexa-1,3-diene-1-sulfonamide

¹H NMR (DMSO-d₆) δ: 10.87 (bs, 1H), 8.07 (d, 1H, J=8 Hz), 7.70-7.45 (m,3H), 7.37-6.96 (m, 9H), 4.43 (s, 1H), 4.25-3.98 (m, 1H), 3.40-2.88 (m,3H), 2.66 (s, 2H), 1.60-1.29 (m, 4H). LC-MS: m/z 488.0 (M+H)⁺

Compound 237 General Procedure 5, Step DN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)phenyl)-2,3-dichlorobenzenesulfonamide

¹H NMR (DMSO-d₆) δ: 11.03 (bs, 1H), 8.05 (d, 1H, J=7.6 Hz), 7.89 (d, 1H,J=8 Hz), 7.54 (d, 1H, J=8 Hz), 7.31-7.11 (m, 7H), 7.07 (d, 2H, J=8.8Hz), 4.43 (s, 1H), 4.23-3.90 (m, 1H), 3.41-2.90 (m, 3H), 2.27 (s, 2H),1.58-1.30 (m, 4H). LC-MS: m/z 520.4 (M+H)⁺

General Procedure 6

Step A:

To a solution of compound 6A (1 eq.) in THF was added pyridine (5 eq.),then aryl-sulfonyl chloride (1.2 eq.). The resulting mixture was heatedat 70° C. under microwave irradiation for 20 minutes, when LC-MS showedthat the reaction was complete. The mixture was then concentrated andpurified by reverse phase chromatography (0-100% MeOH/H₂O) to affordcompound 6B.

Step B:

To a mixture of the corresponding compound 6B (1 eq.) in THF, was addedLiOH (10 eq.), and the mixture was stirred at room temperatureovernight. The reaction mixture was concentrated, the residue dilutedwith water, and extracted with DCM. The aqueous layer was neutralizedwith 1N HCl, then extracted with DCM. The organic layer was separated,concentrated to get the crude product, which was purified by silica gelchromatography to obtain compound 6C.

Step C:

To a round-bottomed flask was added the corresponding compound 6C (1eq.), DMF (5 mL), DIPEA (3.0 eq.), HBTU (1.2 eq.), and compound 6D (1.0eq.) sequentially. The reaction mixture was stirred at room temperatureovernight or until TLC showed that s.m. was consumed. The mixture wasdiluted with brine, extracted with ethyl acetate, the organic layer wasdried with anhydrous Na₂SO₄, filtered, and the filtrate was concentratedin vacuo. The desired product was purified by a standard method.

Compound 185 General Procedure 6, Step CN-(4-(4-hydroxy-4-(pyridin-3-ylmethyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ: 10.41 (bs, 1H), 9.12 (m, 1H), 8.52-8.26 (m, 5H),7.74-7.57 (m, 3H), 7.27-7.24 (m, 1H), 7.11-7.09 (m, 4H), 4.54 (s, 1H),4.06-3.99 (m, 1H), 3.18-2.99 (m, 3H), 2.33 (s, 2H), 1.37-1.34 (m, 4H).LC-MS: m/z 503.6 (M+H)⁺

Compound 189 General Procedure 6, Step CN-(4-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14-9.12 (m, 1H), 8.48-8.47 (m, 2H), 8.31 (dd,2H, J=8.4 Hz & J=7.2 Hz), 8.02 (d, 1H, J=7.2 Hz), 7.65-7.56 (m, 3H),7.25-7.03 (m, 6H), 4.13 (bs, 1H), 3.39-3.23 (m, 4H), 2.87 (s, 2H),1.53-1.28 (m, 4H). LC-MS: m/z 503.6 (M+H)⁺

Compound 207 General Procedure 6, Step CN-(4-(4-hydroxy-4-((6-methylpyridin-2-yl)methyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14-9.13 (m, 1H), 8.50 (bs, 1H), 8.31 (dd, 2H,J=7.2 & J=8 Hz), 8.03 (d, 1H, J=8 Hz), 7.62-7.49 (m, 3H), 7.14 (d, 2H,J=8.4 Hz), 7.09-7.03 (m, 3H), 6.88 (d, 1H, J=7.6 Hz), 5.29 (s, 1H),4.32-4.30 (m, 1H), 3.48-3.21 (m, 3H), 2.82 (s, 2H), 2.50 (s, 3H),1.45-1.33 (m, 4H). LC-MS: m/z 517.6 (M+H)⁺

Compound 146 General Procedure 6, Step CN-(4-(4-((6-fluoropyridin-2-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14-9.13 (m, 1H), 8.511 (bs, 1H), 8.32 (dd,2H, J=7.2 Hz & J=7.2), 8.03 (d, 1H, J=8 Hz), 7.76-7.59 (m, 3H), 7.14 (d,2H, J=8.4 Hz), 7.04 (d, 2H, J=8.4 Hz), 7.00-6.98 (m, 1H), 6.83-6.80 (m,1H), 4.61 (s, 1H), 4.34-4.32 (m, 1H), 3.40-3.19 (m, 3H), 2.86 (s, 2H),1.58-1.43 (m, 4H). LC-MS: m/z 521.6 (M+H)⁺

Compound 168 General Procedure 6, Step CN-(4-(4-((2-fluoropyridin-3-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (400 MHz, CDCl₃) δ: 9.15 (dd, J=4.4, 1.6 Hz, 1H), 8.54 (s, 1H),8.36 (dd, J=7.2, 1.2 Hz, 1H), 8.30 (dd, J=8.4, 1.6 Hz, 1H), 8.12 (d,J=4.4 Hz, 1H), 8.04 (d, J=7.2 Hz, 1H), 7.66-7.56 (m, 3H), 7.18-7.11 (m,3H), 7.06 (d, J=8.5 Hz, 2H), 4.36 (s, 1H), 3.49 (s, 1H), 3.29-3.21 (m,1H), 3.21-3.07 (m, 1H), 2.80 (s, 2H), 2.17 (s, 1H), 1.74-1.60 (m, 2H),1.40-1.29 (m, 2H). LC-MS: m/z 521.6 (M+H)⁺

Compound 143 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (dd, J=4.3, 1.6 Hz, 1H), 8.42 (dd, J=7.3,1.3 Hz, 1H), 8.33 (dd, J=8.3, 1.6 Hz, 1H), 8.06-8.12 (m, 1H), 7.60-7.68(m, 2H), 7.50 (dd, J=7.8, 1.6 Hz, 1H), 7.39 (dd, J=7.7, 1.5 Hz, 1H),7.29-7.32 (m, 1H), 7.22-7.27 (m, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.99 (d,J=9.7 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 4.65 (d, J=13.2 Hz, 1H), 3.58(br. s., 1H), 3.40 (d, J=11.3 Hz, 1H), 3.22-3.35 (m, 1H), 2.93 (br. s.,1H), 2.32 (td, J=13.3, 4.6 Hz, 1H), 2.20 (s, 3H), 2.11 (d, J=12.6 Hz,1H), 1.98 (d, J=13.4 Hz, 1H). LC-MS: m/z 540.6 (M+H)⁺

Compound 193 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-3-fluorophenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (dd, J=4.3, 1.6 Hz, 1H), 8.42 (dd, J=7.3,1.3 Hz, 1H), 8.33 (dd, J=8.3, 1.6 Hz, 1H), 8.06-8.12 (m, 1H), 7.60-7.68(m, 2H), 7.50 (dd, J=7.8, 1.6 Hz, 1H), 7.39 (dd, J=7.7, 1.5 Hz, 1H),7.29-7.32 (m, 1H), 7.22-7.27 (m, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.99 (d,J=9.7 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 4.65 (d, J=13.2 Hz, 1H), 3.58(br. s., 1H), 3.40 (d, J=11.3 Hz, 1H), 3.22-3.35 (m, 1H), 2.93 (br. s.,1H), 2.32 (td, J=13.3, 4.6 Hz, 1H), 2.20 (s, 3H), 2.11 (d, J=12.6 Hz,1H), 1.98 (d, J=13.4 Hz, 1H). LC-MS: m/z 540.6 (M+H)⁺

Compound 104 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.11 (dd, J=4.3, 1.6 Hz, 1H), 8.43 (dd, J=7.3,1.1 Hz, 1H), 8.31 (dd, J=8.3, 1.6 Hz, 1H), 8.04-8.10 (m, 1H), 7.59-7.66(m, 2H), 7.52 (dd, J=7.8, 1.9 Hz, 1H), 7.36 (dd, J=7.5, 1.6 Hz, 1H),7.20-7.30 (m, 3H), 7.13 (s, 1H), 7.03 (dd, J=8.3, 1.6 Hz, 1H), 4.56 (br.s., 1H), 3.61 (br. s., 1H), 3.52 (br. s., 1H), 3.26 (br. s., 1H),2.29-2.43 (m, 1H), 2.11-2.27 (m, 4H), 1.96-2.07 (m, 3H), 1.90 (d, J=7.8Hz, 1H). LC-MS: m/z 536.3 (M+H)⁺

Compound 141 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-3-methylphenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.13-9.19 (m, 1H), 8.48 (br. s., 1H), 8.28-8.41(m, 2H), 8.07 (d, J=8.1 Hz, 1H), 7.57-7.67 (m, 2H), 7.52 (d, J=7.3 Hz,1H), 7.38 (d, J=7.5 Hz, 1H), 7.22-7.27 (m, 1H), 6.92-7.01 (m, 1H), 6.88(d, J=8.1 Hz, 2H), 4.69 (d, J=13.7 Hz, 1H), 3.48 (br. s., 1H), 3.22-3.36(m, 2H), 2.37 (br. s., 1H), 2.21 (br. s., 1H), 2.15 (br. s., 2H),2.02-2.11 (m, 2H), 1.99 (br. s., 1H). LC-MS: m/z 536.3 (M+H)⁺

Compound 170 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (d, J=4.0 Hz, 1H), 8.30-8.42 (m, 2H),8.04-8.12 (m, 1H), 7.59-7.67 (m, 2H), 7.35-7.57 (m, 2H), 7.23-7.34 (m,3H), 6.83-6.99 (m, 2H), 6.36-6.49 (m, 1H), 3.64-3.78 (m, 3H), 3.18-3.35(m, 1H), 3.04 (s, 1H), 2.76 (s, 1H), 2.27-2.40 (m, 1H), 1.90-2.14 (m,4H). LC-MS: m/z 552.3 (M+H)⁺

Compound 209 General Procedure 6, Step CN—(N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-3-cyanophenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.3, 1.6 Hz, 1H), 8.33-8.44 (m,2H), 8.08-8.14 (m, 1H), 7.63-7.70 (m, 2H), 7.49 (dd, J=7.8, 1.6 Hz, 1H),7.36-7.44 (m, 3H), 4.66 (d, J=13.2 Hz, 1H), 3.65 (t, J=12.0 Hz, 2H),3.29-3.41 (m, 2H), 3.21 (br. s., 1H), 2.64 (br. s., 1H), 2.20-2.40 (m,3H), 2.15 (d, J=12.6 Hz, 1H), 2.06 (d, J=7.3 Hz, 1H). LC-MS: m/z 547.7(M+H)⁺.

Compound 263 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-2-(difluoromethoxy)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 2.09 (br. s., 4H) 2.35 (br. s., 2H), 3.30 (br.s., 1H), 3.61 (br. s., 2H), 4.60 (br. s., 1H), 6.21 (t, J=72 Hz 1H),7.04 (s, 1H), 7.17 (dd, J=8.46, 1.75 Hz, 1H), 7.25-7.28 (m, 1H),7.30-7.33 (m, 1H), 7.40 (dd, J=7.79, 1.61 Hz, 1H), 7.51 (dd, J=7.66,1.75 Hz, 1H), 7.61 (dd, J=4.57, 3.76 Hz, 1H), 7.63-7.66 (m, 1H), 7.84(d, J=8.33 Hz, 1H), 8.08 (dd, J=8.33, 1.34 Hz, 1H), 8.30 (dd, J=8.33,1.61 Hz, 1H), 8.43 (dd, J=7.39, 1.48 Hz, 1H), 8.97 (br. s., 1H), 9.14(dd, J=4.30, 1.88 Hz, 1H). LC-MS: m/z 589.0 (M+H)⁺

Compound 151 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-3-(difluoromethoxy)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.21 (br. s., 1H), 8.89 (br. s., 1H), 8.38-8.50(m, 2H), 8.13 (d, J=7.8 Hz, 1H), 7.66-7.75 (m, 2H), 7.50 (br. s., 1H),7.39 (d, J=7.5 Hz, 1H), 7.29-7.33 (m, 1H), 7.21-7.27 (m, 1H), 7.07-7.16(m, 1H), 6.94-7.06 (m, 2H), 6.37 (s, 1H), 4.66 (d, J=14.5 Hz, 1H), 3.50(br. s., 1H), 3.31 (d, J=13.4 Hz, 2H), 2.29 (br. s., 2H), 2.11 (br. s.,2H). LC-MS: m/z 589.0 (M+H)⁺

Compound 136N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-3-(trifluoromethoxy)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15 (dd, J=4.3, 1.3 Hz, 1H), 8.67 (br. s.,1H), 8.41 (dd, J=7.4, 1.2 Hz, 1H), 8.33 (dd, J=8.3, 1.3 Hz, 1H),8.05-8.13 (m, 1H), 7.60-7.69 (m, 2H), 7.45-7.54 (m, 1H), 7.38 (d, J=7.5Hz, 1H), 7.31 (br. s., 1H), 7.20-7.27 (m, 1H), 7.09-7.20 (m, 2H),6.96-7.09 (m, 1H), 4.65 (d, J=13.2 Hz, 1H), 3.43-3.64 (m, 1H), 3.28 (d,J=9.7 Hz, 2H), 3.01 (br. s., 1H), 2.18-2.39 (m, 1H), 2.02-2.18 (m, 2H),1.88-2.02 (m, 1H). LC-MS: m/z 607.1 (M+H)⁺

Compound 218 General Procedure 6, Step C3-fluoro-N-(4-(4-hydroxy-4-phenylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.06 (d, J=2.6 Hz, 1H), 8.36 (dd, J=1.0, 7.2Hz, 1H), 8.24 (s, 1H), 8.07-8.02 (m, 1H), 7.96-7.89 (m, 1H), 7.65 (t,J=7.8 Hz, 1H), 7.51-7.30 (m, 5H), 7.25-7.19 (m, J=8.2 Hz, 2H), 7.14-7.04(m, J=8.5 Hz, 2H), 4.59 (br. s., 1H), 3.71-3.42 (m, 2H), 3.33 (br. s.,1H), 1.90-1.84 (m, 5H). LC-MS: m/z 506.6 (M+H)⁺

Compound 128 General Procedure 6, Step CN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)phenyl)-3-fluoroquinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.04 (d, J=3.0 Hz, 1H), 8.28-8.40 (m, 2H), 8.02(dd, J=8.3, 1.1 Hz, 1H), 7.92 (dd, J=8.2, 2.8 Hz, 1H), 7.63 (t, J=7.8Hz, 1H), 7.22-7.36 (m, 3H), 7.12-7.21 (m, 4H), 7.02-7.12 (m, 2H), 4.36(br. s., 1H), 3.27-3.09 (m, 3H), 2.74 (s, 2H), 1.76 (br. s., 3H), 1.59(br. s., 2H). LC-MS: m/z 520.6 (M+H)⁺

Compound 196 General Procedure 6, Step C6-fluoro-N-(4-(4-hydroxy-4-phenylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.08-9.19 (m, 1H), 8.56 (br. s., 1H), 8.28 (dd,J=8.4, 1.3 Hz, 1H), 8.18 (dd, J=7.6, 2.9 Hz, 1H), 7.61-7.73 (m, 2H),7.44-7.49 (m, 2H), 7.39 (t, J=7.6 Hz, 2H), 7.29-7.34 (m, 1H), 7.21-7.27(m, J=8.5 Hz, 2H), 7.07-7.13 (m, J=8.5 Hz, 2H), 4.58 (br. s., 1H), 3.58(br. s., 1H), 3.51 (br. s., 1H), 3.30 (br. s., 1H), 1.95-2.20 (m, 2H),1.86 (br. s., 3H). LC-MS: m/z 506.6 (M+H)⁺

Compound 223 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-6-fluoroquinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 8.94-9.05 (m, 1H), 8.33 (dd, J=8.3, 1.6 Hz,1H), 8.20 (dd, J=8.6, 3.0 Hz, 1H), 7.76-7.83 (m, 1H), 7.67-7.74 (m, 1H),7.57 (dd, J=8.3, 4.3 Hz, 1H), 7.26-7.39 (m, 2H), 7.18-7.26 (m, 1H),7.09-7.18 (m, J=8.6 Hz, 2H), 6.96-7.09 (m, J=8.6 Hz, 2H), 4.45 (br. s.,1H), 2.71 (br. s., 2H), 1.47-1.68 (m, 6H). LC-MS: m/z 540.6 (M+H)⁺

Compound 220 General Procedure 6, Step CN-(4-(4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-2-methylphenyl)-5-fluoroquinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.19 (dd, J=4.3, 1.6 Hz, 1H), 8.63 (dd, J=8.5,1.7 Hz, 1H), 8.36 (dd, J=8.3, 5.9 Hz, 1H), 7.78 (dd, J=8.6, 4.3 Hz, 1H),7.34-7.46 (m, 2H), 7.09-7.20 (m, 4H), 7.04 (dd, J=8.3, 1.6 Hz, 1H), 4.58(br. s., 1H), 4.48 (d, J=10.2 Hz, 1H), 3.52 (br. s., 3H), 2.06-2.36 (m,7H). LC-MS: m/z 556.7 (M+H)⁺

Compound 232 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-3,5-difluorophenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15 (dd, J=4.3, 1.6 Hz, 1H), 8.75 (br. s.,1H), 8.45 (dd, J=7.4, 1.2 Hz, 1H), 8.36 (dd, J=8.3, 1.3 Hz, 1H), 8.13(d, J=8.1 Hz, 1H), 7.63-7.72 (m, 2H), 7.50 (dd, J=7.8, 1.6 Hz, 1H), 7.39(dd, J=7.7, 1.5 Hz, 1H), 7.31 (d, J=7.5 Hz, 1H), 7.25 (td, J=7.5, 1.6Hz, 1H), 6.69-6.80 (m, 2H), 4.67 (d, J=10.7 Hz, 1H), 3.53-3.68 (m, 1H),3.26-3.46 (m, 2H), 2.94 (br. s., 1H), 2.32-2.00 (m, 4H). LC-MS: m/z558.1 (M+H)⁺

Compound 246 General Procedure 6, Step CN-(4-(4-(ethoxymethyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.10-9.20 (m, 1H), 8.55 (br. s., 1H), 8.26-8.43(m, 2H), 8.05 (d, J=8.2 Hz, 1H), 7.55-7.70 (m, 2H), 7.12-7.20 (m, J=8.5Hz, 2H), 7.03-7.12 (m, J=8.5 Hz, 2H), 4.37 (br. s., 1H), 3.53 (q, J=6.9Hz, 2H), 3.45 (br. s., 1H), 3.36 (br. s., 1H), 3.26 (s, 3H), 2.29-2.41(m, 1H), 1.65 (br. s., 3H), 1.55 (br. s., 1H), 1.20 (td, J=7.0, 2.2 Hz,3H). LC-MS: m/z 470.6 (M+H)⁺

Compound 225 General Procedure 6, Step CN-[4-[4-hydroxy-4-(2-methoxyethyl)piperidine-1-carbonyl]phenyl]quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.28 (br. s., 3H), 1.58 (br. s., 2H), 1.73-1.79(m, 4H), 2.04 (d, J=4.99 Hz, 1H), 3.25 (br. s., 1H), 3.45 (br. s., 2H),3.65 (br. s., 2H), 4.38 (br. s., 1H), 7.11 (m, J=8.22 Hz, 2H), 7.18 (m,J=8.51 Hz, 2H), 7.61-7.72 (m, 2H), 8.09 (d, J=8.22 Hz, 1H), 8.36-8.44(m, 2H), 8.86 (br. s., 1H), 9.19-9.24 (m, 1H). LC-MS: m/z 470.6 (M+H)⁺

Compound 144 General Procedure 6, Step CN-(4-(4-(cyclopropylmethyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.19 (d, J=2.8 Hz, 1H), 8.67 (s, 1H), 8.40 (dd,J=7.3, 1.3 Hz, 1H), 8.35 (d, J=7.2 Hz, 1H), 8.07 (dd, J=8.2, 1.2 Hz,1H), 7.70-7.58 (m, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H),4.37 (s, 1H), 3.42 (d, J=38.4 Hz, 2H), 3.20 (s, 1H), 1.62 (d, J=56.1 Hz,4H), 1.42 (s, 2H), 0.80-0.66 (m, 1H), 0.59-0.46 (m, 2H), 0.10 (q, J=4.9Hz, 2H). LC-MS: m/z 466.6 (M+H)⁺

Compound 176 General Procedure 6, Step CN-(4-(4-((2,2-difluorocyclopropyl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.3, 1.6 Hz, 1H), 8.64 (br. s.,1H), 8.28-8.43 (m, 2H), 8.07 (dd, J=8.1, 1.3 Hz, 1H), 7.54-7.71 (m, 2H),7.13-7.21 (m, 2H), 7.06-7.13 (m, 2H), 4.23-4.51 (m, 1H), 3.49 (d, J=13.2Hz, 1H), 3.34 (br. s., 1H), 3.23 (br. s., 1H), 1.58 (br. s., 2H),1.38-1.56 (m, 5H), 0.77-1.02 (m, 3H). LC-MS: m/z 502.6 (M+H)⁺

Compound 210 General Procedure 6, Step CN-(6-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-2-methylpyridin-3-yl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14 (dd, J=4.4, 1.6 Hz, 1H), 8.46 (dd, J=7.3,1.3 Hz, 1H), 8.34 (dd, J=8.3, 1.5 Hz, 1H), 8.09-8.14 (m, 1H), 7.78 (d,J=8.3 Hz, 1H), 7.61-7.71 (m, 2H), 7.50 (dd, J=7.8, 1.5 Hz, 1H), 7.39(dd, J=7.7, 1.4 Hz, 1H), 7.31 (s, 1H), 7.22-7.28 (m, 1H), 4.63 (d,J=13.1 Hz, 1H), 3.84 (d, J=13.6 Hz, 1H), 3.54-3.64 (m, 1H), 3.33 (td,J=12.9, 2.6 Hz, 1H), 2.46 (s, 3H), 2.24-2.38 (m, 2H), 1.97-2.16 (m, 2H),1.60-1.75 (m, 2H). LC-MS: m/z 537.7 (M+H)⁺

Compound 261 General Procedure 6, Step CN-(3-cyano-4-(4-hydroxy-4-phenylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.20 (dd, J=4.3, 1.6 Hz, 1H), 8.43 (dd, J=12.5,7.8 Hz, 1H), 8.43 (dd, J=15.6, 7.9 Hz, 1H), 8.14 (dd, J=8.2, 1.2 Hz,1H), 7.66-7.74 (m, 2H), 7.45-7.49 (m, 4H), 7.39 (d, J=7.6 Hz, 4H), 4.64(d, J=13.5 Hz, 2H), 3.74 (d, J=7.0 Hz, 2H), 3.27 (br. s., 1H), 3.13 (br.s., 1H), 2.02 (dd, J=14.2, 4.0 Hz, 4H). LC-MS: m/z 512.6 (M+H)⁺

Compound 197 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)naphthalene-1-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 8.70 (d, J=8.3 Hz, 1H), 8.25 (d, J=7.0 Hz, 1H),8.05 (d, J=8.1 Hz, 1H), 7.94 (d, J=7.8 Hz, 1H), 7.57-7.70 (m, 3H),7.46-7.55 (m, 2H), 7.36-7.43 (m, 1H), 7.19-7.27 (m, 3H), 7.00 (d, J=8.6Hz, 2H), 4.64 (br. s., 1H), 3.56 (br. s., 1H), 3.51 (s, 1H), 3.31 (br.s., 1H), 2.36 (br. s., 1H), 2.15-2.23 (m, 1H), 1.91-2.13 (m, 3H). LC-MS:m/z 521.0 (M+H)⁺

Compound 102 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)chroman-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 7.68 (d, J=7.8 Hz, 1H), 7.54 (dd, J=7.8, 1.6Hz, 1H), 7.39 (dd, J=7.7, 1.5 Hz, 1H), 7.29-7.33 (m, 2H), 7.19-7.28 (m,2H), 7.17 (d, J=8.6 Hz, 2H), 6.87 (t, J=7.8 Hz, 1H), 4.63 (br. s., 1H),4.36-4.47 (m, 2H), 3.61 (br. s., 2H), 3.31 (br. s., 1H), 2.81 (t, J=6.3Hz, 2H), 2.39 (br. s., 1H), 2.14-2.32 (m, 1H), 2.01-2.12 (m, 3H),1.87-2.01 (m, 1H), 1.71 (d, J=14.2 Hz, 1H). LC-MS: m/z 527.7 (M+H)⁺

Compound 186 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzofuran-7-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 7.75-7.88 (m, 3H), 7.52 (dd, J=7.9, 1.5 Hz,1H), 7.40 (dd, J=7.5, 1.3 Hz, 1H), 7.30-7.35 (m, 2H), 7.21-7.28 (m, 3H),7.10 (d, J=8.6 Hz, 2H), 6.90 (d, J=2.1 Hz, 1H), 4.64 (br. s., 1H), 3.59(br. s., 1H), 3.51 (s, 1H), 3.31 (br. s., 1H), 2.91 (s, 1H), 2.14-2.31(m, 1H), 2.09 (br. s., 1H), 1.86-2.07 (m, 2H). LC-MS: m/z 511.0 (M+H)⁺

Compound 157 General Procedure 6, Step CN-(3-chloro-4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (d, J=4.0 Hz, 1H), 8.42 (d, J=7.3 Hz, 1H),8.35 (d, J=8.1 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 8.03 (d, J=5.4 Hz, 1H),7.61-7.69 (m, 2H), 7.47-7.55 (m, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.19-7.25(m, 1H), 7.16 (s, 1H), 6.95-7.13 (m, 3H), 4.63-4.73 (m, 1H), 3.61 (d,J=11.0 Hz, 1H), 3.21-3.35 (m, 2H), 2.35 (td, J=13.2, 4.6 Hz, 2H), 2.10(t, J=11.3 Hz, 2H). LC-MS: m/z 556.5 (M+H)⁺

Compound 222 General Procedure 6, Step CN-(2-chloro-4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.13 (dd, J=4.3, 1.6 Hz, 1H), 8.92 (br. s.,1H), 8.48 (dd, J=7.4, 1.2 Hz, 1H), 8.29 (dd, J=8.3, 1.6 Hz, 1H),8.05-8.12 (m, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.58-7.68 (m, 2H), 7.51 (dd,J=7.8, 1.6 Hz, 1H), 7.40 (dd, J=7.7, 1.5 Hz, 1H), 7.30-7.34 (m, 1H),7.23-7.27 (m, 1H), 7.19 (dd, J=8.6, 1.9 Hz, 1H), 4.60 (br. s., 1H), 3.61(br. s., 2H), 3.31 (br. s., 1H), 2.91 (br. s., 1H), 2.14-2.27 (m, 1H),1.91-2.14 (m, 3H). LC-MS: m/z 556.5 (M+H)⁺

Compound 253 General Procedure 6, Step CN-(4-(4-hydroxy-4-(3-hydroxypropyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ: 10.40 (s, 1H), 9.13 (dd, J=4.1, 1.8 Hz, 1H), 8.52(dd, J=8.5, 1.8 Hz, 1H), 8.42 (dd, J=7.3, 1.2 Hz, 1H), 8.29 (dd, J=8.2,1.5 Hz, 1H), 7.63-7.85 (m, 2H), 7.01-7.16 (m, 4H), 4.39 (br. s., 1H),4.25 (s, 1H), 3.17 (br. s., 2H), 3.07 (br. s., 1H), 1.39-1.51 (m, 3H),1.34 (dd, J=9.4, 5.6 Hz, 5H). LC-MS: m/z 470.2 (M+H)⁺

Compound 224 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-2-fluoroquinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 8.33-8.48 (m, 2H), 8.02-8.07 (m, 2H), 7.60 (t,J=7.8 Hz, 1H), 7.49 (dd, J=7.8, 1.3 Hz, 1H), 7.37 (dd, J=7.7, 1.5 Hz,1H), 7.28 (br. s., 1H), 7.21-7.25 (m, 2H), 7.20 (s, 1H), 7.11-7.16 (m,2H), 3.56 (br. s., 3H), 2.18-2.38 (m, 2H), 1.64 (br. s., 4H). LC-MS: m/z540.6 (M+H)⁺

Compound 229 General Procedure 6, Step C5-fluoro-N-(4-(4-(6-fluoro-2-methylpyridin-3-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.21 (dd, J=4.3, 1.6 Hz, 1H), 8.57 (dd, J=8.6,1.6 Hz, 1H), 8.34-8.45 (m, 2H), 7.68-7.74 (m, 2H), 7.27 (s, 1H),7.17-7.22 (m, J=8.3 Hz, 2H), 7.05-7.11 (m, J=8.3 Hz, 2H), 6.70 (dd,J=8.5, 3.6 Hz, 1H), 3.46-3.65 (m, 2H), 1.91-2.08 (m, 4H), 1.62-1.82 (m,4H). LC-MS: m/z 539.7 (M+H)⁺

Compound 115 General Procedure 6, Step CN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)-3-fluorophenyl)quinoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ: 10.67 (s, 1H), 9.119-9.110 (m, 1H), 8.48 (dd, 2H,J=8 Hz & J=7.2 Hz), 8.29 (d, 1H, J=8.4 Hz), 7.77-7.69 (m, 2H), 7.25-7.06(m, 6H), 6.94-6.90 (m, 2H), 4.45 (s, 1H), 4.12-4.09 (m, 1H), 3.17-2.98(m, 3H), 2.68 (s, 2H), 1.39-1.23 (m, 4H). LC-MS: m/z 520.6 (M+H)⁺

Compound 163 General Procedure 6, Step CN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)-2-fluorophenyl)quinoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ: 9.88 (bs, 1H), 9.08-9.06 (m, 1H), 8.57-8.54 (m, 1H),8.29 (t, 2H, J=8.4 Hz), 7.31-7.17 (m, 6H), 7.08-7.03 (m, 2H), 4.44 (s,1H), 4.09-4.01 (m, 1H), 3.21-3.02 (m, 3H), 2.65 (s, 2H), 1.41-1.23 (m,4H). LC-MS: m/z 520.6 (M+H)⁺

Compound 101 General Procedure 6, Step CN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)-2-methylphenyl)quinoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ: 9.35 (s, 1H), 9.3-9.12 (m, 1H), 8.57 (d, 1H, J=8.4Hz), 8.28 (dd, 2H, J=8.8 Hz & J=7.2 Hz), 7.77-7.68 (m, 2H), 7.25-7.17(m, 5H), 7.04-6.95 (m, 3H), 4.08 (bs, 1H), 3.39-3.37 (m, 1H), 3.22-3.01(m, 3H), 2.65 (s, 2H), 2.04 (s, 3H), 1.40-1.24 (m, 4H). LC-MS: m/z 516.6(M+H)⁺

Compound 112 General Procedure 6, Step CN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)-3-methoxyphenyl)quinoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ: 10.26 (bs, 1H), 9.13 (bs, 1H), 8.49-8.21 (m, 2H),7.71-7.69 (m, 2H), 7.23-7.17 (m, 5H), 6.80-6.61 (m, 3H), 4.08-4.07 (m,1H), 3.54 (s, 3H), 3.18 (s, 2H), 2.92-2.84 (m, 2H), 2.66-2.62 (m, 2H),1.45-1.34 (m, 4H). LC-MS: m/z 532.6 (M+H)⁺

Compound 131 General Procedure 6, Step CN-(4-(4-benzyl-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14-9.13 (m, 1H), 8.36-8.27 (m, 2H), 8.04-8.02(m, 1H), 7.62-7.56 (m, 2H), 7.33-7.27 (m, 2H), 7.16-7.15 (m, 3H),7.14-7.13 (m, 2H), 4.36 (bs, 1H), 3.72-3.66 (m, 1H), 3.44-3.42 (m, 2H),3.18-3.12 (m, 1H), 2.74 (s, 2H), 1.48-1.42 (m, 4H). LC-MS: m/z 502.6(M+H)⁺

Compound 226 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)naphthalen-1-yl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.27 (d, J=4.3 Hz, 2H), 8.39-8.48 (m, 2H),8.29-8.38 (m, 1H), 8.12 (dd, J=7.5, 4.3 Hz, 1H), 7.83-7.92 (m, 1H),7.65-7.76 (m, 2H), 7.48-7.57 (m, 3H), 7.39 (d, J=7.5 Hz, 1H), 7.20-7.27(m, 2H), 7.16 (d, J=2.4 Hz, 1H), 4.88 (br. s., 1H), 3.33-3.59 (m, 2H),3.17-3.33 (m, 2H), 2.56 (d, J=5.1 Hz, 1H), 2.45 (d, J=4.8 Hz, 1H), 1.85(d, J=11.0 Hz, 1H), 1.73 (d, J=16.1 Hz, 1H). LC-MS: m/z 573.1 (M+H)⁺

Compound 169 General Procedure 6, Step CN-(4-(4-(2,3-difluorobenzyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (400 MHz, CDCl₃) δ: 9.16 (dd, J=4.2, 1.4 Hz, 1H), 8.38 (d, J=7.3Hz, 1H), 8.31 (d, J=8.4 Hz, 1H), 8.06 (d, J=8.2 Hz, 1H), 7.69-7.57 (m,2H), 7.17-7.13 (m, 2H), 7.13-7.05 (m, 3H), 7.04-6.92 (m, 2H), 6.73 (s,1H), 4.39 (s, 1H), 3.87 (s, 1H), 3.40 (s, 1H), 3.23 (s, 1H), 2.84-2.74(m, 2H), 1.74-1.60 (m, 2H), 1.71-1.59 (m, 4H). LC-MS: m/z 538.6 (M+H)⁺

Compound 158 General Procedure 6, Step C5-fluoro-N-(4-(4-(2-fluorobenzyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.19 (s, 1H), 8.53 (s, 1H), 8.41-8.33 (m, 1H),7.66 (s, 1H), 7.24 (dd, J=13.3, 6.0 Hz, 2H), 7.17 (dd, J=14.0, 7.9 Hz,3H), 7.13-7.08 (m, 2H), 7.05 (d, J=7.6 Hz, 3H), 4.37 (s, 1H), 3.49-3.05(m, 3H), 2.82 (s, 2H), 1.78-1.50 (m, 4H). LC-MS: m/z 538.1 (M+H)⁺

Compound 120 General Procedure 6, Step CN-(4-(4-(2,6-difluorobenzyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (dd, J=4.3, 1.9 Hz, 1H), 8.58 (br. s.,1H), 8.35 (dd, J=18.0, 7.8 Hz, 1H), 8.35 (dd, J=17.9, 7.9 Hz, 1H), 8.06(dd, J=8.3, 1.3 Hz, 1H), 7.57-7.69 (m, 2H), 7.19-7.27 (m, 1H), 7.14-7.19(m, 2H), 7.05-7.11 (m, 2H), 6.86-6.94 (m, 2H), 4.35-4.45 (m, 1H),3.41-3.53 (m, 1H), 3.31 (br. s., 1H), 3.08-3.20 (m, 1H), 2.88-2.92 (m,1H), 2.82 (s, 1H), 1.70 (br. s., 1H), 1.64 (dd, J=11.1, 6.9 Hz, 2H),1.43-1.58 (m, 2H). LC-MS: m/z 538.7 (M+H)⁺

Compound 109 General Procedure 6, Step CN-(4-(4-hydroxy-4-(2-(trifluoromethyl)benzyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15 (dd, J=4.3, 1.6 Hz, 1H), 8.60 (br. s.,1H), 8.27-8.40 (m, 2H), 8.04 (dd, J=8.2, 1.2 Hz, 1H), 7.55-7.71 (m, 3H),7.43-7.54 (m, 2H), 7.31-7.40 (m, 1H), 7.12-7.21 (m, J=8.6 Hz, 2H),7.01-7.12 (m, J=8.6 Hz, 2H), 4.41 (br. s., 1H), 3.46 (d, J=9.1 Hz, 1H),3.27 (br. s., 1H), 3.05 (br. s., 1H), 2.98 (s, 2H), 1.83 (br. s., 1H),1.66 (br. s., 2H), 1.56 (br. s., 2H), 1.45 (br. s., 1H). LC-MS: m/z570.7 (M+H)⁺

Compound 117 General Procedure 6, Step CN-(4-(4-hydroxy-4-neopentylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.20 (d, J=2.9 Hz, 1H), 8.73 (s, 1H), 8.41 (dd,J=7.3, 1.2 Hz, 1H), 8.36 (d, J=7.3 Hz, 1H), 8.08 (dd, J=8.2, 1.2 Hz,1H), 7.70-7.60 (m, 2H), 7.18 (d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H),4.36 (s, 1H), 3.39 (d, J=33.4 Hz, 2H), 3.16 (s, 1H), 1.75-1.57 (m, 4H),1.49 (s, 2H), 1.05 (s, 9H). LC-MS: m/z 482.7 (M+H)⁺

Compound 178 General Procedure 6, Step CN-(4-(4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (DMSO-d₆) δ: 10.79 (s, 1H), 9.66 (s, 1H), 8.50 (d, J=8.1 Hz, 1H),8.12 (d, J=7.5 Hz, 1H), 7.65 (t, J=7.8 Hz, 1H), 7.41 (t, J=7.4 Hz, 1H),7.33 (q, J=8.2 Hz, 1H), 7.16-7.24 (m, 3H), 7.11-7.15 (m, 2H), 4.31 (br.s., 1H), 3.32-3.13 (br. s., 3H), 2.00 (d, J=7.3 Hz, 2H), 1.63 (br. s.,2H). LC-MS: m/z 530.6 (M+H)⁺

Compound 215 General Procedure 6, Step CN-(4-(4-(2-(difluoromethyl)phenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (br. s., 1H), 8.19 (d, J=7.8 Hz, 1H),8.08-8.14 (m, 1H), 7.93-8.03 (m, 1H), 7.84 (d, J=4.8 Hz, 1H), 7.48-7.60(m, 2H), 7.44 (br. s., 1H), 7.37 (br. s., 1H), 7.23 (d, J=8.3 Hz, 2H),7.10-7.18 (m, 2H), 4.91-5.06 (m, 1H), 4.54-4.73 (m, 1H), 3.80 (br. s.,2H), 3.72 (br. s., 1H), 3.45-3.65 (m, 2H), 2.32-2.61 (m, 2H). LC-MS: m/z544.7 (M+H)⁺

Compound 241 General Procedure 6, Step CN-(4-(4-hydroxy-4-(2-hydroxy-2-methylpropyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (dd, J=4.3, 1.8 Hz, 1H), 8.56 (br. s.,1H), 8.38 (dd, J=7.3, 1.3 Hz, 1H), 8.31 (dd, J=8.4, 1.6 Hz, 1H), 8.06(dd, J=8.3, 1.1 Hz, 1H), 7.57-7.67 (m, 2H), 7.17 (d, J=8.5 Hz, 2H), 7.08(d, J=8.5 Hz, 2H), 4.31 (br. s., 1H), 3.40 (br. s., 2H), 3.21 (br. s.,1H), 1.86-1.65 (br.m, 6H), 1.36 (s, 6H). LC-MS: m/z 484.6 (M+H)⁺

Compound 167 General Procedure 6, Step CN-(4-(4-butyl-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (d, J=2.6 Hz, 1H), 8.59 (br. s., 1H),8.25-8.42 (m, 2H), 8.06 (d, J=7.9 Hz, 1H), 7.55-7.68 (m, 2H), 7.17 (d,J=8.2 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 4.33 (br. s., 1H), 3.42 (br. s.,1H), 3.34 (br. s., 1H), 3.19 (br. s., 1H), 1.60 (br. s., 2H), 1.37-1.37(m, 11H), 0.9 (t, J=6.6 Hz, 3H). LC-MS: m/z 468.6 (M+H)⁺

Compound 132 General Procedure 6, Step CN-(4-(4-hydroxy-4-((1-methylcyclopropyl)methyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.15-8.23 (m, 1H), 8.06-8.13 (m,1H), 7.92 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.16-7.24 (m, J=8.3 Hz, 2H),7.07-7.14 (m, J=8.3 Hz, 2H), 4.34 (br. s., 1H), 3.29 (br. s., 3H), 1.66(br. s., 2H), 1.47 (s, 2H), 1.33 (br. s., 1H), 1.28 (s, 1H), 1.17 (s,3H), 0.25-0.38 (m, 4H). LC-MS: m/z 480.6 (M+H)⁺

Compound 121 General Procedure 6, Step CN-(4-(4-hydroxy-4-((1-methylcyclopropyl)methyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.16 (dd, J=4.3, 1.6 Hz, 1H), 8.56 (br. s.,1H), 8.38 (dd, J=7.5, 1.3 Hz, 1H), 8.32 (dd, J=8.3, 1.6 Hz, 1H), 8.06(dd, J=8.2, 1.2 Hz, 1H), 7.58-7.67 (m, 2H), 7.14-7.20 (m, J=8.6 Hz, 2H),7.04-7.11 (m, J=8.6 Hz, 2H), 4.36 (br. s., 1H), 3.44 (br. s., 1H), 3.36(br. s., 1H), 3.17 (br. s., 1H), 1.74 (br. s., 1H), 1.70 (br. s., 1H),1.63 (d, J=6.7 Hz, 3H), 1.46 (s, 2H), 1.17 (s, 3H), 0.24-0.37 (m, 4H).LC-MS: m/z 480.6 (M+H)⁺

Compound 198 General Procedure 6, Step CN-(4-(4-(cyclopropylmethyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (br. s., 1H), 8.19 (d, J=7.8 Hz, 1H), 8.10(d, J=7.3 Hz, 1H), 7.94 (s, 1H), 7.54 (t, J=7.7 Hz, 1H), 7.20 (br. s.,2H), 7.12 (br. s., 2H), 4.38 (br. s., 1H), 3.51 (br. s., 1H), 3.36 (br.s., 2H), 2.06 (br. s., 2H), 1.69 (d, J=8.6 Hz, 2H), 1.43 (br. s., 2H),0.74 (br. s., 1H), 0.53 (d, J=7.5 Hz, 2H), 0.11 (d, J=4.3 Hz, 2H).LC-MS: m/z 472.6 (M+H)⁺

Compound 201 General Procedure 6, Step CN-(4-(4-(cyclobutylmethyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-5-fluoroquinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.21 (dd, J=4.2, 1.5 Hz, 1H), 8.57 (dd, J=8.5,1.5 Hz, 1H), 8.37 (dd, J=8.2, 5.7 Hz, 2H), 7.70 (dd, J=8.5, 4.3 Hz, 1H),7.26 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H),4.33 (s, 1H), 3.54-3.08 (m, 4H), 2.49 (dd, J=15.5, 7.7 Hz, 1H),2.13-2.01 (m, 2H), 1.91 (dd, J=18.4, 9.4 Hz, 1H), 1.83-1.75 (m, 1H),1.60 (d, J=7.0 Hz, 5H), 1.48-1.51 (m, 2H), 1.42 (s, 2H), 1.27 (s, 2H).LC-MS: m/z 498.6 (M+H)⁺

Compound 134 General Procedure 6, Step CN-(4-(4-hydroxy-4-neopentylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.10 (d,J=8.3 Hz, 1H), 7.91 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.18-7.22 (m, J=8.3Hz, 2H), 7.09-7.13 (m, J=8.3 Hz, 2H), 1.65 (br. s., 4H), 1.50 (s, 2H),1.28 (s, 4H), 1.05 (s, 9H). LC-MS: m/z 488.6 (M+H)⁺

Compound 187 General Procedure 6, Step C5-fluoro-N-(4-(4-hydroxy-4-neopentylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.23 (dd, J=4.3, 1.5 Hz, 1H), 8.60 (dd, J=8.5,1.5 Hz, 1H), 8.44 (s, 1H), 8.39 (dd, J=8.3, 5.7 Hz, 1H), 7.72 (dd,J=8.5, 4.3 Hz, 1H), 7.31-7.26 (m, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.08 (d,J=8.5 Hz, 2H), 4.36 (s, 1H), 3.50-3.02 (m, 3H), 1.70-1.58 (m, 4H), 1.49(s, 2H), 1.06 (d, J=8.3 Hz, 9H). LC-MS: m/z 500.71 (M+H)⁺

Compound 208 General Procedure 6, Step C5-fluoro-N-(4-(4-hydroxy-4-(2-(trifluoromethyl)benzyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.46-1.64 (m, 3H), 1.81 (br. s., 1H), 2.98 (s,2H), 3.05 (br. s., 1H), 3.28 (br. s., 1H), 3.38-3.51 (m, 1H), 4.42 (br.s., 1H), 7.06 (m, J 8.33 Hz, 2H), 7.16 (m, J=8.33 Hz, 2H), 7.23-7.27 (m,1H), 7.32-7.39 (m, 1H), 7.44-7.53 (m, 2H), 7.64-7.72 (m, 2H), 8.37 (dd,J=8.19, 5.78 Hz, 1H), 8.41 (s, 1H), 8.55 (dd, J=8.60, 1.61 Hz, 1H), 9.20(dd, J=4.30, 1.61 Hz, 1H). LC-MS: m/z 588.7 (M+H)⁺

Compound 412 General Procedure 6, Step CN-(4-(4-hydroxy-4-(2-(trifluoromethyl)benzyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.44 (br. s., 1H), 1.51-1.70 (m, 3H), 2.99 (s,2H), 3.06 (br. s., 1H), 3.30 (br. s., 1H), 3.39-3.47 (m, 1H), 4.42 (br.s., 1H), 7.10 (m, J=8.60 Hz, 2H), 7.17 (m, J=8.60 Hz, 2H), 7.33-7.40 (m,1H), 7.45-7.56 (m, 3H), 7.67 (d, J=7.79 Hz, 1H), 8.10 (dd, J=7.52, 1.07Hz, 1H), 8.17 (dd, J=8.06, 0.81 Hz, 1H), 8.22 (s, 1H), 9.29 (s, 1H).LC-MS: m/z 576.7 (M+H)⁺

Compound 181 General Procedure 6, Step CN-(4-(4-hydroxy-4-(2-methylallyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.30 (s, 1H), 8.18 (dd, J=8.1, 0.8 Hz, 1H),8.08-8.14 (m, 1H), 8.06 (s, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.17-7.24 (m,2H), 7.06-7.15 (m, 2H), 4.96-5.03 (m, 1H), 4.78 (s, 1H), 4.36 (br. s.,1H), 3.44 (br. s., 1H), 3.35 (br. s., 1H), 3.17 (br. s., 1H), 2.18-2.22(m, 2H), 1.82 (s, 3H), 1.63 (br. s., 2H), 1.48 (br. s., 2H). LC-MS: m/z472.69 (M+H)⁺

Compound 414 General Procedure 6, Step C

¹H NMR (CHLOROFORM-d) δ: 9.14 (d, J=5.6 Hz, 1H), 8.80 (br. s., 1H),8.43(d, J=7.3 Hz, 1H), 8.36 (d, J=8.3 Hz, 1H), 8.13 (d, J=8.1 Hz, 1H),7.62-7.72 (m, 2H), 7.53 (s, 1H), 7.23-7.33 (m, 2H), 6.84 (t, J=56 Hz,1H), 4.36 (br. s., 1H), 3.42 (br. s., 2H), 3.22 (br. s., 1H), 1.84 (dt,J=12.9, 6.4 Hz, 1H), 1.64 (br. s., 2H), 1.52 (br. s., 2H), 1.42 (d,J=5.9 Hz, 2H), 0.98 (d, J=6.7 Hz, 6H). LC-MS: m/z 518.7 (M+H)⁺

Compound 415 General Procedure 6, Step C(E)-N-(4-(4-(3,3-difluoroprop-1-en-1-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.21 (dd, J=4.4, 1.7 Hz, 1H), 8.85 (s, 1H),8.40 (ddd, J=9.9, 7.9, 1.4 Hz, 2H), 8.09 (dd, J=8.2, 1.2 Hz, 1H),7.72-7.61 (m, 2H), 7.19 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H),6.28-5.84 (m, 3H), 4.43 (s, 1H), 3.51 (s, 1H), 3.30 (d, J=69.3 Hz, 2H),1.82-1.52 (m, 4H). LC-MS: m/z 488.63 (M+H)⁺

Compound 386 General Procedure 6, Step CN-(4-(4-hydroxy-4-((2,2,2-trifluoroethoxy)methyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (METHANOL-d₄) δ: 9.47 (s, 1H), 8.31 (dd, J=8.1, 1.1 Hz, 1H),8.07-8.14 (m, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.11-7.25 (m, 4H), 4.18-4.37(m, 1H), 3.98 (q, J=9.0 Hz, 2H), 3.48 (s, 2H), 3.35-3.43 (m, 2H), 3.19(br. s., 1H), 1.65 (br. s., 2H), 1.38-1.59 (m, 2H). LC-MS: m/z 530.7(M+H)⁺

Compound 387 General Procedure 6, Step CN-(4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.10 (d,J=7.3 Hz, 1H), 7.92 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.16-7.24 (m, J=8.1Hz, 2H), 7.06-7.15 (m, J=8.3 Hz, 2H), 5.37 (br. s., 1H), 4.36 (br. s.,1H), 3.34 (br. s., 2H), 3.22 (br. s., 1H), 1.93-2.08 (m, 2H), 1.56-1.71(m, 9H). LC-MS: m/z 510.7 (M+H)⁺

Compound 388 General Procedure 6, Step C4-hydroxy-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinazoline-8-sulfonamide

¹H NMR (METHANOL-d₄) δ: 0.97 (d, J=6.72 Hz, 6H), 1.39 (d, J=5.91 Hz,2H), 1.49 (br. s., 2H), 1.56 (br. s., 1H), 1.66 (br. s., 1H), 1.80-1.91(m, 1H), 7.21-7.26 (m, 4H), 7.58 (t, J=7.92 Hz, 1H), 8.28 (s, 1H), 8.39(ddd, J=7.72, 6.11, 1.48 Hz, 2H). LC-MS: m/z 485.7 (M+H)⁺

Compound 389 General Procedure 6, Step CN-(4-(4-(4,4-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (400 MHz, CHLOROFORM-d) δ: 1.22-1.37 (m, 2H), 1.59 (br. s., 6H),1.75-1.94 (m, 2H), 3.19 (d, J=4.57 Hz, 1H), 3.32 (br. s., 1H), 3.47 (br.s., 1H), 5.84 (t, J=4.30 Hz, 1H), 7.11 (m, J=8.33 Hz, 2H), 7.19 (m,J=8.33 Hz, 2H), 7.54 (t, J=7.92 Hz, 1H), 7.96 (s, 1H), 8.10 (d, J=7.52Hz, 1H), 8.19 (d, J=8.06 Hz, 1H), 9.31 (s, 1H). LC-MS: m/z 510.5 (M+H)⁺

Compound 390 General Procedure 6, Step CN-(4-(4-hydroxy-4-(2-(trifluoromethyl)allyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (dd, J=8.1, 0.8 Hz, 1H),8.10 (dd, J=7.5, 1.1 Hz, 1H), 7.92 (s, 1H), 7.53-7.59 (m, 1H), 7.17-7.23(m, J=8.6 Hz, 2H), 7.09-7.14 (m, J=8.6 Hz, 2H), 5.93 (d, J=1.3 Hz, 1H),5.60 (s, 1H), 4.42 (br. s., 1H), 3.50 (br. s., 1H), 3.35 (br. s., 1H),3.17 (br. s., 1H), 2.42 (s, 2H), 1.65 (br. s., 2H), 1.45 (br. s., 2H).LC-MS: m/z 526.7 (M+H)⁺

Compound 421 General Procedure 6, Step CN-(4-(4-hydroxy-4-(3,3,3-trifluoro-2-methylpropyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=7.5 Hz, 1H), 8.10 (d,J=7.5 Hz, 1H), 7.98 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.15-7.24 (m, J=8.3Hz, 2H), 7.05-7.15 (m, J=8.3 Hz, 2H), 4.34 (br. s., 1H), 3.51 (s, 1H),3.12-3.41 (m, 2H), 2.44 (d, J=7.0 Hz, 1H), 1.87 (dd, J=14.9, 2.0 Hz,1H), 1.58 (br.s., 4H), 1.42 (dd, J=14.9, 7.4 Hz, 2H), 1.21 (d, J=7.0 Hz,3H). LC-MS: m/z 528.6 (M+H)⁺

Compound 442 General Procedure 6, Step CN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)naphthalen-1-yl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.27 (d, J=4.3 Hz, 2H), 8.39-8.48 (m, 2H),8.29-8.38 (m, 1H), 8.12 (dd, J=7.5, 4.3 Hz, 1H), 7.83-7.92 (m, 1H),7.65-7.76 (m, 2H), 7.48-7.57 (m, 3H), 7.39 (d, J=7.5 Hz, 1H), 7.20-7.27(m, 2H), 7.16 (d, J=2.4 Hz, 1H), 4.88 (br. s., 1H), 3.33-3.59 (m, 2H),3.17-3.33 (m, 2H), 2.56 (d, J=5.1 Hz, 1H), 2.45 (d, J=4.8 Hz, 1H), 1.85(d, J=11.0 Hz, 1H), 1.73 (d, J=16.1 Hz, 1H). LC-MS: m/z 573.1 (M+H)⁺

General Procedure 7

Step A:

To a mixture of RBr (0.08 mol) and magnesium turnings (4.8 g, 0.2 mol)in dry tetrahydrofuran (80 mL) was added a crystal of iodine and themixture was stirred at room temperature until complete reaction hadoccurred. To this mixture was added tert-butyl4-oxopiperidine-1-carboxylate (7.7 g, 0.039 mol) in tetrahydrofuran (20mL) at 0° C. After 1 h at 0° C., and 3 h at room temperature thereaction mixture was diluted with ammonium chloride solution, and themixture was extracted with ethyl acetate. After drying over Na₂SO₄, thesolvent was removed in vacuo and the residue was purified via flashchromatography with 20% ethyl acetate/hexane to afford the titlecompound 7B.

Step B:

A solution of the corresponding compound 7B (3.0 mmol) in the solutionof HCl in 1,4-dioxane (3M, 5 mL) was stirred at room temperature for 3hours. The solution was evaporated to dryness under reduced pressure togive the crude product 3 which was used in the next step without furtherpurification.

Step C:

To a solution of compound 7C (0.2 mmol) in DMF (5 mL) was added HBTU (91mg, 0.24 mmol) and the mixture was stirred at r.t. for 20 min, thenIntermediate F (0.2 mmol) and DIPEA (0.6 mmol) were added. Afterstirring overnight, the reaction was partitioned between satd. Na₂CO₃solution and DCM. The organic layer was separated and washed with waterand brine, dried over Na₂SO₄ and concentrated, and then purified by astandard method to give title product 7D.

Compound 392 General Procedure 7, Step CN-(4-(4-hydroxy-4-isopentylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 10.76 (s, 1H), 9.65 (s, 1H), 8.49 (d, J=8.1 Hz,1H), 8.10 (d, J=7.5 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.16 (d, J=8.3 Hz,2H), 7.09 (d, J=8.4 Hz, 2H), 4.18 (s, 1H), 4.08 (s, 1H), 3.16 (m, 3H),1.05-1.3 (m, 9H), 0.82 (d, J=6.6 Hz, 6H). LC-MS: m/z 488.6 (M+H)⁺

Compound 393 General Procedure 7, Step CN-(4-(4-(4,4-difluorobut-3-en-1-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (400 MHz, CHLOROFORM-d) δ: 0.89 (d, J=6.98 Hz, 2H), 1.56 (d,J=8.60 Hz, 2H), 1.70 (br. s., 2H), 1.76 (br. s., 2H), 2.02-2.13 (m, 2H),4.09-4.23 (m, 1H), 7.11 (d, J=8.33 Hz, 2H), 7.19 (d, J=8.33 Hz, 2H),7.54 (t, J=7.79 Hz, 1H), 8.02-8.14 (m, 2H), 8.19 (d, J=8.33 Hz, 1H),9.30 (s, 1H). LC-MS: m/z 508.5 (M+H)⁺

Compound 394 General Procedure 7, Step CN-(4-(4-hydroxy-4-(4,4,4-trifluorobutyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.3 Hz, 1H), 8.10 (d,J=6.7 Hz, 1H), 7.98 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.16-7.21 (m, J=8.6Hz, 2H), 7.07-7.15 (m, J=8.3 Hz, 2H), 4.37 (br. s., 1H), 3.46 (br. s.,1H), 3.34 (br. s., 1H), 3.21 (br. s., 1H), 2.10 (br. s., 3H), 1.54 (br.s., 4H), 1.33 (br. s., 4H). LC-MS: m/z 528.8 (M+H)⁺

Compound 395 General Procedure 7, Step CN-(4-(4-hydroxy-4-(3,4,4-trifluorobut-3-enyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.38 (br. s., 3H), 1.50 (br. s., 1H), 1.54-1.63(m, 2H), 2.33 (br. s., 1H), 2.39 (br. s., 1H), 2.98-3.14 (m, 2H),3.14-3.28 (m, 2H), 4.07 (br. s., 1H), 7.10 (m, J=8.60 Hz, 2H), 7.17 (m,J=8.60 Hz, 2H), 7.64 (t, J=7.92 Hz, 1H), 8.11 (d, J=6.72 Hz, 1H), 8.50(d, J=8.06 Hz, 1H), 9.65 (s, 1H), 10.76 (s, 1H). LC-MS: m/z 526.7 (M+H)⁺

Compound 233 General Procedure 7, Step CN-(4-(4-hydroxy-4-(3,3,3-trifluoropropyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.20 (d, J=7.3 Hz, 1H), 8.10 (d,J=7.8 Hz, 1H), 7.94 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.20 (d, J=8.6 Hz,2H), 7.12 (d, J=8.6 Hz, 2H), 4.33 (s, 1H), 3.73 (s, 1H), 3.53-3.44 (m,1H), 3.19 (s, 2H), 2.29-2.18 (m, 2H), 1.55-1.50 (m, 2H), 1.47 (d, J=6.7Hz, 2H), 0.9 (t, J=6.8 Hz, 2H). LC-MS: m/z 514.6 (M+H)⁺

Compound 212 General Procedure 7, Step CN-(4-(4-(cyclobutylmethyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.32 (s, 1H), 8.24-8.15 (m, 1H), 8.13-8.07 (m,1H), 7.96 (s, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.19 (d, J=8.5 Hz, 2H), 7.12(d, J=8.5 Hz, 2H), 4.34 (s, 1H), 3.70 (dd, J=10.2, 6.4 Hz, 2H), 3.16(dd, J=7.4, 4.2 Hz, 2H), 2.55-2.43 (m, 1H), 1.62 (s, 1H), 1.43-1.45 (m,5H), 1.40-1.36 (m, 2H), 1.26-1.31 (m, 4H). LC-MS: m/z 486.6 (M+H)⁺

General Procedure 8

Step A:

To a solution of the corresponding methyl 4-aminobenzoate (8A, 2.5 mmol)in 20 mL of DCM was added pyridine (600 mg, 7.5 mmol) andbenzo[c][1,2,5]thiadiazole-4-sulfonyl chloride (585 mg, 2.5 mmol). Theresulting mixture was stirred at 50° C. overnight. After removal of DCM,the residue was partitioned between water and EtOAc. The organic layerwas washed with 2 N HCl, water and brine, dried over Na₂SO₄ andconcentrated to give crude product 8B, which was confirmed by LCMS, andused in the next reaction without further purification.

Step B:

To a solution of the corresponding compound 8B (1.0 mmol) in AcOH/H₂O (8mL/3 mL) at 70° C. was added zinc powder (975 mg, 15 mmol) and theresulting suspension was stirred at 70° C. for 1 h. The solid wasfiltered off and washed with EtOAc. The filtrate was partitioned betweensatd. NaHCO₃ and EtOAc. The organic layer was separated and washed withwater and brine, dried over anhydrous Na₂SO₄ and concentrated to givecrude product 8C, which was confirmed by LCMS, and used in the nextreaction without further purification.

Step C:

To a solution of the corresponding compound 8C (0.9 mmol) inethanol/water (30 mL/4 mL) was added glyoxal sodium bisulfite hydrate(975 mg, 15 mmol) and the resulting suspension was stirred at 100° C.overnight. The solvent was removed in vacuo and the residue waspartitioned between water and EtOAc. The organic layer was separated andwashed with water and brine, dried over Na₂SO₄ and concentrated,purified by flash column to give title product 8D, which was confirmedby LCMS.

Step D:

To a solution of the corresponding compound 8D (0.2 mmol) in EtOH/H₂O(10 mL/3 mL) was added LiOH.H₂O (37 mg, 0.9 mmol) and the resultingsuspension was stirred at 70° C. overnight. The solvent was concentratedand the residue was partitioned between aqueous 2 N HCl and EtOAc. Theorganic layer was separated and washed with water and brine, dried overNa₂SO₄ and concentrated to give the desired crude product 8E, which wasconfirmed by LCMS, and used in subsequent reaction without furtherpurification.

Step E:

To a solution of compound 8E (0.2 mmol) and in DCM (10 mL) was addedHBTU (91 mg, 0.24 mmol) and stirred at r.t. for 20 min, then thecorresponding compound 8F (0.2 mmol) and DIPEA (0.6 mmol) were added.After stirring for 30 mins, the reaction was partitioned between satd.Na₂CO₃ solution and DCM. The organic layer was separated and washed withwater and brine, dried over Na₂SO₄ and concentrated, and then purifiedby a standard method to give title product 8G.

Compound 251 General Procedure 8, Step EN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-2-fluorophenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.06 (s, 2H), 8.46 (d, J=7.3 Hz, 1H), 8.33-8.40(m, 2H), 7.83-7.88 (m, 1H), 7.75 (t, J=8.1 Hz, 1H), 7.51 (d, J=7.5 Hz,1H), 7.39 (d, J=7.5 Hz, 1H), 7.29 (br. s., 1H), 7.25 (m, 1H), 7.11 (d,J=8.3 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 4.58 (br. s., 1H), 3.58 (br. s.,2H), 3.31 (br. s., 1H), 2.36 (br. s., 2H), 2.18 (br. s., 2H). LC-MS: m/z542.0 (M+H)⁺

Compound 262 General Procedure 8, Step EN-(4-(4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-2-fluorophenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.06 (s, 2H), 8.47 (d, J=8.5 Hz, 1H), 8.34-8.40(m, 2H), 7.83-7.89 (m, 1H), 7.76 (t, J=8.2 Hz, 1H), 7.24 (t, J=7.0 Hz,1H), 7.08-7.16 (m, 3H), 6.99 (d, J=10.5 Hz, 1H), 4.59 (br. s., 1H), 3.57(br. s., 2H), 3.28 (br. s., 1H), 2.25 (br. s., 2H), 2.13 (br. s., 1H),1.88 (br. s., 2H). LC-MS: m/z 543.5 (M+H)⁺

Compound 160 General Procedure 8, Step EN-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.07 (s, 2H), 8.45 (dd, J=7.3, 1.3 Hz, 1H),8.35 (dd, J=8.5, 1.2 Hz, 1H), 8.03 (s, 1H), 7.82-7.88 (m, 1H), 7.16-7.21(m, J=8.6 Hz, 2H), 7.06-7.11 (m, J=8.3 Hz, 2H), 4.33 (br. s., 1H), 3.35(br. s., 2H), 3.19 (br. s., 1H), 1.82 (dt, J=12.8, 6.3 Hz, 1H), 1.50(br. s., 4H), 1.40 (d, J=5.9 Hz, 2H), 0.97 (d, J=6.7 Hz, 6H). LC-MS: m/z469.5 (M+H)⁺

Compound 243 General Procedure 8, Step EN-(4-(4-hydroxy-4-phenylpiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.03-9.08 (m, 2H), 8.45 (dd, J=7.3, 1.5 Hz,1H), 8.34 (dd, J=8.5, 1.5 Hz, 1H), 8.14 (s, 1H), 7.84 (dd, J=8.4, 7.5Hz, 1H), 7.41-7.46 (m, 2H), 7.33-7.38 (m, 2H), 7.29-7.31 (m, 1H),7.25-7.28 (m, 1H), 7.19-7.23 (m, J=8.5 Hz, 2H), 7.07-7.11 (m, J=8.5 Hz,2H), 4.54 (br. s., 1H), 3.53 (br. s., 2H), 3.20-3.36 (m, 1H), 1.93 (br.s., 2H), 1.84 (br. s., 2H). LC-MS: m/z 488.6 (M+H)⁺

Compound 162 General Procedure 8, Step EN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.05-9.10 (m, 2H), 8.45 (dd, J=7.5, 1.3 Hz,1H), 8.36 (dd, J=8.6, 1.3 Hz, 1H), 8.02-8.09 (m, 1H), 7.85 (dd, J=8.3,7.5 Hz, 1H), 7.52 (dd, J=7.8, 1.9 Hz, 1H), 7.38 (dd, J=7.8, 1.6 Hz, 1H),7.25-7.28 (m, 1H), 7.24 (s, 1H), 7.21-7.23 (m, 1H), 7.10 (d, J=8.6 Hz,2H), 4.60 (d, J=10.7 Hz, 1H), 3.56 (br. s., 2H), 3.50 (s, 1H), 1.86-2.09(m, 2H), 1.72 (br. s., 2H). LC-MS: m/z 523.6 (M+H)⁺

Compound 119 General Procedure 8, Step EN-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)-2-methylphenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.02-9.07 (m, 2H), 8.51 (d, J=7.3 Hz, 1H), 8.38(d, J=8.3 Hz, 1H), 7.89 (t, J=7.9 Hz, 1H), 7.76 (s, 1H), 7.50-7.54 (m,1H), 7.39 (dd, J=7.5, 1.3 Hz, 1H), 7.29-7.32 (m, 1H), 7.22-7.28 (m, 2H),7.16 (s, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.60 (br. s., 1H), 3.61 (br. s.,1H), 3.55 (br. s., 1H), 3.31 (d, J=11.3 Hz, 1H), 2.35 (d, J=7.5 Hz, 1H),2.25 (s, 3H), 2.20 (d, J=14.8 Hz, 1H), 2.01-2.12 (m, 1H), 1.97 (br. s.,1H). LC-MS: m/z 537.6 (M+H)⁺

Compound 175 General Procedure 8, Step EN-(4-(4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)-2-methylphenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.05 (dd, J=9.2, 1.6 Hz, 2H), 8.51 (dd, J=7.3,1.3 Hz, 1H), 8.38 (dd, J=8.4, 1.1 Hz, 1H), 7.89 (dd, J=8.3, 7.5 Hz, 1H),7.76 (s, 1H), 7.22-7.27 (m, 1H), 7.03-7.17 (m, 4H), 4.58 (br. s., 1H),3.60 (br. s., 1H), 3.39-3.57 (m, 1H), 3.24 (br. s., 1H), 2.05-2.19 (m,1H), 1.83 (br. s., 1H), 1.75 (br. s., 2H). LC-MS: m/z 538.6 (M+H)⁺

Compound 213 General Procedure 8, Step EN-(3-(difluoromethoxy)-4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.07 (d, J=5.4 Hz, 2H), 8.48 (d, J=7.3 Hz, 1H),8.38 (d, J=8.6 Hz, 1H), 8.04 (s, 1H), 7.85-7.93 (m, 1H), 6.99-6.90 (m,3H), 6.36 (t, J=73.2 Hz, 1H), 4.39 (br. s., 1H), 3.25-3.16 (m, 3H), 1.82(m, 1H), 1.63 (m., 5H), 0.98 (d, J=6.7 Hz, 6H). LC-MS: m/z 535.8 (M+H)⁺

Compound 114 General Procedure 8, Step EN-(4-(4-hydroxy-4-(2-(trifluoromethyl)benzyl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.60 (br. s., 4H), 3.01 (s, 2H), 3.12 (br. s.,1H), 3.30 (br. s., 1H), 3.48 (br. s., 1H), 4.47 (br. s., 1H), 7.08 (m,J=7.79 Hz, 2H), 7.20 (m, J=8.06 Hz, 2H), 7.39 (dd, J=8.33, 3.76 Hz, 1H),7.47-7.53 (m, 2H), 7.69 (d, J=7.79 Hz, 1H), 7.82-7.89 (m, 1H), 7.99 (s,1H), 8.36 (dd, J=8.46, 1.21 Hz, 1H), 8.45 (dd, J=7.39, 1.21 Hz, 1H),9.08 (s, 2H). LC-MS: m/z 571.7 (M+H)⁺

Compound 221 General Procedure 8, Step EN-(4-(4-hydroxy-4-(3,3,3-trifluoropropyl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.12 (d, J=1.9 Hz, 1H), 9.03 (d, J=1.9 Hz, 1H),8.50 (dd, J=7.3, 1.3 Hz, 1H), 8.32 (dd, J=8.3, 1.3 Hz, 1H), 7.91 (dd,J=8.3, 7.5 Hz, 1H), 7.15-7.26 (m, 4H), 3.18 (br. s., 1H), 2.25 (td,J=11.1, 5.9 Hz, 2H), 1.62-1.78 (m, 3H), 1.56 (br. s., 1H), 1.46 (br. s.,2H), 1.31 (d, J=2.1 Hz, 1H). LC-MS: m/z 509.62 (M+H)⁺

Compound 130 General Procedure 8, Step EN-(4-(4-hydroxy-4-neopentylpiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.08 (s, 2H), 8.45 (dd, J=7.4, 1.2 Hz, 1H),8.36 (dd, J=8.6, 1.3 Hz, 1H), 8.00 (s, 1H), 7.85 (dd, J=8.3, 7.5 Hz,1H), 7.15-7.22 (m, J=8.3 Hz, 2H), 7.03-7.11 (m, J=8.6 Hz, 2H), 4.36 (br.s., 1H), 3.40 (br. s., 2H), 3.17 (dd, J=12.6, 5.9 Hz, 2H), 1.62 (br. s.,4H), 1.49 (s, 2H), 1.05 (s, 9H). LC-MS: m/z 483.6 (M+H)⁺

Compound 188 General Procedure 8, Step EN-(4-(4-(cyclopropylmethyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.07 (q, J=1.7 Hz, 2H), 8.45 (dd, J=7.3, 1.3Hz, 1H), 8.35 (dd, J=8.6, 1.3 Hz, 1H), 8.06 (s, 1H), 7.85 (dd, J=8.5,7.4 Hz, 1H), 7.15-7.22 (m, J=8.3 Hz, 2H), 7.04-7.13 (m, J=8.3 Hz, 2H),4.37 (br. s., 1H), 3.49 (br. s., 1H), 3.27 (br. s., 3H), 1.76 (br. s.,1H), 1.51-1.66 (m, 3H), 1.41 (d, J=6.4 Hz, 2H), 0.65-0.80 (m, 1H),0.46-0.58 (m, 2H), 0.05-0.13 (m, 2H). LC-MS: m/z 467.6 (M+H)⁺

Compound 396 General Procedure 8, Step EN-(4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.08 (s, 2H), 8.45 (dd, J=7.3, 1.1 Hz, 1H),8.36 (dd, J=8.5, 1.2 Hz, 1H), 8.03 (s, 1H), 7.86 (dd, J=8.3, 7.5 Hz,1H), 7.14-7.24 (m, J=8.1 Hz, 2H), 7.04-7.13 (m, J=8.1 Hz, 2H), 4.33 (br.s., 1H), 3.51 (s, 1H), 3.28 (br. s., 3H), 1.88-2.02 (m, 2H), 1.56-1.69(m, 9H). LC-MS: m/z 505.6 (M+H)⁺

Compound 397 General Procedure 8, Step EN-(4-(4-hydroxy-4-(4,4,4-trifluorobutyl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.08 (s, 2H), 8.45 (dd, J=7.3, 1.3 Hz, 1H),8.36 (dd, J=8.6, 1.3 Hz, 1H), 8.04 (s, 1H), 7.82-7.89 (m, 1H), 7.16-7.22(m, J=8.6 Hz, 2H), 7.06-7.12 (m, J=8.6 Hz, 2H), 4.35 (br. s., 1H), 3.43(br. s., 1H), 3.34 (br. s., 1H), 3.17 (br. s., 1H), 2.04-2.14 (m, 2H),1.48-1.58 (m, 4H), 1.32 (br. s., 2H), 1.24 (br. s., 2H). LC-MS: m/z523.7 (M+H)⁺

Compound 398 General Procedure 8, Step EN-(4-(4-hydroxy-4-(3,4,4-trifluorobut-3-enyl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.44 (br. s., 1H), 1.49-1.65 (m, 3H), 2.31-2.45(m, 2H), 2.57 (d, J=6.45 Hz, 1H), 3.10-3.38 (m, 3H), 7.08 (m, J=8.60 Hz,2H), 7.18 (m, J=8.60 Hz, 2H), 7.84 (dd, J=8.33, 7.52 Hz, 1H), 8.34 (dd,J=8.46, 1.21 Hz, 1H), 8.45 (dd, J=7.39, 1.21 Hz, 1H), 9.03-9.10 (m, 2H).LC-MS: m/z 521.7 (M+H)⁺

Compound 399 General Procedure 8, Step EN-(4-(4-(4,4-difluorobut-3-en-1-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (400 MHz, CHLOROFORM-d) δ: 0.79-0.93 (m, 2H), 1.51-1.57 (m, 3H),1.59-1.74 (m, 4H), 1.98-2.17 (m, 2H), 3.33 (br. s., 2H), 3.50 (s, 1H),4.08-4.24 (m, 1H), 7.08 (m, J=8.33 Hz, 2H), 7.19 (m, J=8.33 Hz, 2H),7.85 (dd, J=8.46, 7.39 Hz, 1H), 8.04 (s, 1H), 8.36 (dd, J=8.46, 1.21 Hz,1H), 8.45 (dd, J=7.39, 1.21 Hz, 1H), 9.08 (s, 2H). LC-MS: m/z 503.5(M+H)⁺

Compound 400 General Procedure 8, Step EN-(4-(4-(4,4-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (400 MHz, CHLOROFORM-d) δ: 1.25-1.29 (m, 2H), 1.51-1.69 (m, 7H),1.78-1.87 (m, 2H), 3.06-3.24 (m, 1H), 3.24-3.36 (m, 1H), 3.41 (br. s.,1H), 4.32 (br. s., 1H), 5.81 (t, J=4.30 Hz, 1H), 7.08 (m, J=8.60 Hz,2H), 7.18 (m, J=8.33 Hz, 2H), 7.84 (dd, J=8.33, 7.52 Hz, 1H), 8.12 (s,1H), 8.34 (dd, J=8.46, 1.21 Hz, 1H), 8.45 (dd, J=7.39, 1.21 Hz, 1H),8.98-9.14 (m, 2H). LC-MS: m/z 505.5 (M+H)⁺

General Procedure 9

Step A: tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (9B)

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25 mmol)in BuOH (20 mL) was added potassium tert-butoxide (4.125 g, 18.75 mmol).The mixture was stirred at 50° C. for 1 h. Then trimethyl sulfoxoniumiodide (11 g, 50 mmol) was added to the mixture, and the resultingreaction mixture was stirred at 50° C. overnight. When TLC showed thats.m. was consumed, the mixture was cooled and filtered. The filtrate wasconcentrated to give the crude product which was used in the next stepwithout further purification.

¹H NMR (CHLOROFORM-d) δ: 3.75 (d, J=13.8 Hz, 2H), 3.45 (dd, J=13.2, 9.4,3.8 Hz, 2H), 2.72 (s, 2H), 2.01-2.07 (m, 2H), 1.78-1.86 (m, 2H), 1.50(s, 9H)

Step B: tert-butyl 4-(ethoxymethyl)-4-hydroxypiperidine-1-carboxylate(9C)

To anhydrous EtOH (20 mL) was added slowly NaH (124 mg, 52 mmol) at 0°C., and after the addition was complete the mixture was stirred for 1.5h. Then tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (9B, 45mmol) was added, and the resulting mixture was stirred at 50° C. for 1h, when TLC showed that s.m. was consumed. Then the mixture wasneutralized with 1N aq. HCl, and concentrated. The residue was purifiedby prep-TLC to give the desired product 9C as colorless oil (600 mg) ¹HNMR (METHANOL-d⁴) δ: 3.78 (d, J=12.6 Hz, 2H), 3.51 (q, J=7.0 Hz, 2H),3.22-3.29 (m, 2H), 3.15 (br. s., 2H), 1.48-1.60 (m, 4H), 1.43 (s, 9H),1.18 (t, J=7.0 Hz, 3H).

Step C: 4-(ethoxymethyl)piperidin-4-ol (9D)

To a solution of tert-butyl4-(ethoxymethyl)-4-hydroxypiperidine-1-carboxylate (9C, 1 eq.) in DCMwas added TFA (10 eq.). The mixture was stirred at r.t. for 0.5 hr, whenTLC showed that s.m. was consumed. The mixture was concentrated to givethe crude product which was used to the next step without furtherpurification. LC-MS: m/z 160.2 (M+H)⁺

General Procedure 10

Step A:

To a solution of the corresponding bromobenzene (4.7 mmol) in 30 mL ofanhydrous THF was added dropwise n-BuLi (7.04 mmol) at −78° C. under N₂.After stirring for 1 h at −78° C., tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate (7.04 mmol) in THF (5 mL) wasadded drop wise to the above obtained solution at −78° C. under N₂. Theresulting mixture was stirred at −78° C. under N₂ for 2 h, then allowedto warm to r.t. and stirred overnight. The reaction mixture was cooledto −78° C. and quenched by satd. NH₄Cl solution, then the resultingmixture was extracted with EtOAc (50 mL, 30 mL). The combined organicphase was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to give the title compound 10B.

Step B:

A solution of compound 10B (1.62 mmol) in 13 mL of 6N HCl in dioxane wasstirred at room temperature for 30 min. The reaction mixture wasconcentrated in vacuo to give the title product 10C as a yellow liquidwhich was used in the next step directly.

General Procedure 11

Step A: tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (11B)

To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (10 g. 50.2mmol), allyl bromide (10.8 mL, 124 mmol) in THF (10 mL), and saturatedammonium chloride solution (50 mL) was added Zn dust (6.5 g, 100 mmol)portionwise below 10° C. After addition was complete, the reactionmixture was stirred overnight, when TLC indicated consumption of s.m.The reaction mixture was diluted with water (50 mL) and acidified withseveral drops of 10% H₂SO₄ to pH=6. The reaction mixture was extractedwith EtOAc (3×200 mL). The organic layers were combined and washed witha saturated solution of NaHCO₃, brine and evaporated, to give the crudeproduct which was purified by chromatography to give title compound 11Bas colorless oil.

¹H NMR (CHLOROFORM-d) δ: 5.77-5.92 (m, 1H), 5.05-5.21 (m, 2H), 3.76 (br.s., 2H), 3.05-3.22 (m, 2H), 2.21 (d, J=7.6 Hz, 2H), 2.01 (br. s., 1H),1.50 (dd, J=7.2, 4.0 Hz, 3H), 1.47 (s, 1H), 1.43 (s, 9H).

Step B: tert-butyl4-((2,2-difluorocyclopropyl)methyl)-4-hydroxypiperidine-1-carboxylate(11C)

To a sealed tube was added tert-butyl4-allyl-4-hydroxypiperidine-1-carboxylate 11B (280 mg, 1.16 mmol), Nat(112 mg, 0.74 mmol), trimethyl(trifluoromethyl)silane (0.6 mL) and THF(10 mL). The tube was sealed, and then the mixture was stirred at 80° C.overnight. The resulting mixture was diluted with DCM, filtered, and thefiltrate was concentrated in vacuo to give the crude product 11C whichwas used for next step without further purification. LC-MS: m/z 292.3(M+H)⁺

Step C: 4-((2,2-difluorocyclopropyl)methyl)piperidin-4-ol (11D)

To a solution of compound 11C (1 eq.) in DCM, was added TFA (10 eq.),the reaction mixture was stirred at room temperature for about 2 hours,when TLC detected no s.m. The reaction mixture was concentrated toafford the desired product 11D. The crude product was used for the nextstep directly without further purification. LC-MS: m/z 192.3 (M+H)⁺

General Procedure 12

Step A: tert-butyl 4-hydroxy-4-(2-methylallyl)piperidine-1-carboxylate(12B)

t-butyl-4-oxopiperidine-1-carboxylate (10 g, 0.05 mol) was dissolved in3-bromo-2-methylprop-1-ene (16.9 g, 0.126 mol), THF (100 mL) andsaturated ammonium chloride solution (500 mL). The reaction was cooledto 10° C. and zinc dust (6.6 g, 0.01 mol) was added portionwise. Afteraddition, the reaction mixture was stirred overnight, when TLC(heptane/EtOAc 7:1) indicated that the reaction was complete. Thereaction mixture was then diluted with water and acidified with 10%H₂SO₄ to pH 6. The reaction mixture was extracted with ethyl acetate(3×50 mL). The organic layers were combined and washed with saturatedsolution of NaHCO₃, brine and evaporated to give tert-butyl4-hydroxy-4-(2-methylallyl)piperidine-1-carboxylate (12.28 g). ¹H NMR(CHLOROFORM-d) δ: 4.94-5.04 (m, 1H), 4.80 (s, 1H), 3.85 (dt, J=13.0, 3.4Hz, 2H), 3.08-3.26 (m, 2H), 2.21 (s, 2H), 1.86 (s, 3H), 1.52-1.60 (m,4H), 1.43-1.50 (m, 9H).

Step B: tert-butyl4-hydroxy-4-((1-methylcyclopropyl)methyl)piperidine-1-carboxylate (12C)

To CH₂Cl₂ (20 mL) at 0° C. was added 1M solution of diethylzinc inhexane (11.75 mL, 11.75 mmol), followed by dropwise addition of asolution of trifluoroacetic acid (0.6 mL, 7.83 mmol) in CH₂Cl₂ (8 mL).After stirring for 15 min, a solution of diiodomethane (0.65 mL, 7.83mmol) in CH₂Cl₂ (8 mL) was added. The mixture was stirred for 15 min anda clear solution resulted. tert-Butyl4-hydroxy-4-(2-methylallyl)piperidine-1-carboxylate (12B) (1 g, 3.92mmol) was added and the mixture was stirred at room temperatureovernight. After quenching with 0.1 M aqueous HCl (50 mL), the CH₂Cl₂layer was separated, washed with brine, dried (Na₂SO₄) and concentratedto give the crude product, which was used directly for the next stepwithout purification.

Step C: 4((1-methylcyclopropyl)methyl)piperidin-4-ol (12D)

To a solution of compound 12C (1 eq.) in DCM, was added TFA (10 eq.),the reaction mixture was stirred at room temperature for about 2 hours,when TLC detected no s.m. The reaction mixture was concentrated toafford the desired product 12D. The crude product was used for the nextstep directly without further purification. LC-MS: m/z 170.3 (M+H)⁺

General Procedure 13

Step A: tert-butyl 4-hydroxy-4-(3-hydroxypropyl)piperidine-1-carboxylate(13B)

A mixture of BH₃ in THF (21 mL, 21.0 mmol) was added slowly to a mixtureof tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (500 mg, 2.07mmol) and THF (5 mL) at 0° C. under nitrogen, and then stirred for 30min. The resulting mixture was allowed to warm to room temperature andstirred overnight. The mixture was cooled to 0° C. and 3N sodiumhydroxide (1 mL) was added followed by the addition of 30% hydrogenperoxide (1 mL). The resulting mixture was allowed to warm to roomtemperature and stirred for 2.5 hours. The mixture was then treated withwater (10 mL) and extracted with EA (3×20 mL). The combined organicextracts were dried over Na₂SO₄ and the solvent was removed in vacuo.The residue was purified by column chromatography on silica gel with(30% EtOAc/PE) to give tert-butyl 4-hydroxy-4-(3-hydroxypropyl)piperidine-1-carboxylate 13B (629 mg) as a colorless oil. ¹H NMR(CHLOROFORM-d) δ: 3.65 (t, J=5.7 Hz, 4H), 3.36 (br. s., 2H), 3.16 (br.s., 2H), 1.63-1.71 (m, 2H), 1.53-1.62 (m, 4H), 1.41-1.48 (m, 9H).

Step B: 4-(3-hydroxypropyl)piperidin-4-ol (13C)

To a solution of compound 2 (1 eq.) in DCM, was added TFA (10 eq.), thereaction mixture was stirred at room temperature for about 2 hours, whenTLC detected no s.m. The reaction mixture was concentrated to afford thedesired product 3. The crude product was used for the next step directlywithout further purification. LC-MS: m/z 160.2 (M+H)⁺

General Procedure 14

Step A: tert-butyl4-(cyclopropylmethyl)-4-hydroxypiperidine-1-carboxylate (14B)

To a suspension of 4,4′-di-tert-butylbiphenyl (DTBB, 30.33 mg, 0.114mmol) and Li (56.7 mg, 8.09 mmol) in 50 mL of anhydrous THF was addeddropwise a solution of (bromomethyl)cyclopropane (307.9 mg, 2.28 mmol)and tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.5 mmol) inanhydrous THF (5 mL) at −78° C. under N₂. The resulting mixture wasstirred at −78° C. under N₂ for 8 h. The reaction mixture was quenchedby satd. NH₄Cl solution at −78° C. The resulting mixture was extractedwith EtOAc (50 mL×2). The combined organic phase was washed with brine,dried over anhy. Na₂SO₄ and concentrated in vacuo. Column chromatography(15% PE/EtOAc) afforded 262.5 mg of title compound as a colorless oil.¹H NMR (CHLOROFORM-d) δ: 3.90-3.78 (m, 2H), 3.25-3.12 (m, 2H), 1.60 (dd,J=9.4, 4.3 Hz, 4H), 1.48 (s, 9H), 1.42 (d, J=6.9 Hz, 2H), 0.82-0.70 (m,1H), 0.57-0.47 (m, 2H), 0.16-0.06 (m, 2H).

Step B: 4-(cyclopropylmethyl)piperidin-4-ol (14C)

To a solution of compound 14B (1 eq.) in DCM, was added TFA (10 eq.),the reaction mixture was stirred at room temperature for about 2 hours,when LCMS detected no s.m. The reaction mixture was concentrated toafford the desired product 14C. The crude product was used for the nextstep directly without further purification. LC-MS: m/z 156.2 (M+H)⁺

General Procedure 15

Step A:

Sodium (90 mg, 3.9 mmol) was added (in small pieces) into2,2,2-trifluoroethanol (2 mL) at room temperature, then the mixture wasstirred at room temperature until Na was totally consumed, and theresulting mixture was then added dropwise into a solution of tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate (500 mg, 2.35 mmol) in 10 mLof anhydrous THF at room temperature. After the addition was complete,the mixture was stirred at 60° C. overnight when TLC (petroleum ether:ethyl acetate=2:1) (I₂ stained) indicated formation of a new spot, andconsumption of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate. Theresulting mixture was then cooled to room temperature, H₂O was added toquench the reaction, and the mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous Na₂SO₄, and concentrated togive crude title compound which was used in the next step withoutfurther purification.

General Procedure 16

Step A: tert-butyl-4-(but-3-en-1-yl)-4-hydroxypiperidine-1-carboxylate(16B)

To a mixture of 4-bromobut-1-ene (10.9 g, 0.08 mol) and magnesiumturnings (4.8 g, 0.2 mol) in dry tetrahydrofuran (80 mL) was added acrystal of iodine and the mixture was stirred at room temperature untilcomplete reaction had occurred. To this mixture was added tert-butyl4-oxopiperidine-1-carboxylate (7.7 g, 0.039 mol) in tetrahydrofuran (20mL) at 0° C. After 1 h at 0° C., and 3 h at room temperature thereaction mixture was diluted with ammonium chloride solution andextracted with ethyl acetate. After drying over Na₂SO₄, the solvent wasremoved in vacuo and the residue was purified via flash chromatographywith 25% ethyl acetate/hexane to afford the title compound 16B (3.63 g)as an oil. ¹H NMR (CHLOROFORM-d) δ 5.84 (d, J=6.7 Hz, 1H), 4.89-5.11 (m,2H), 3.16 (br. s., 2H), 2.16 (d, J=9.4 Hz, 2H), 1.48-1.66 (m, 6H), 1.45(s, 9H).

Step B: tert-butyl-4-acetoxy-4-(but-3-en-1-yl)piperidine-1-carboxylate(16C)

A solution oftert-butyl-4-(but-3-en-1-yl)-4-hydroxypiperidine-1-carboxylate (3.7 g,14.51 mmol) in dichloromethane (20 mL) was treated withdimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL,43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), stirred overnight at20° C. The solvent was removed under reduced pressure and the residuewas partitioned between water and ethyl acetate. The aqueous layer wasextracted twice with ethyl acetate. Combined organic extracts werewashed with water, dried (Na₂SO₄) and filtered. The filtrate wasconcentrated under reduced pressure, purified by flash chromatography toprovide the title compound 16C as colorless oil (3.4 g).

Step C: tert-butyl-4-acetoxy-4-(3-oxobutyl)piperidine-1-carboxylate(16D)

To a solution oftert-butyl-4-acetoxy-4-(but-3-en-1-yl)piperidine-1-carboxylate (1 g,3.36 mmol) in DMF (6 mL) and H₂O (2 mL) was added CuCl (0.77 g, 7.73mmol) and PdCl₂ (0.16 g, 0.91 mmol) and the resulting suspension wasstirred under an oxygen atmosphere at room temperature for 24 h. Theinsoluble materials were removed by filtration, and washed with ethylacetate. The filtrate was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel to give 16D (540 mg) as a colorless oil. ¹HNMR (CHLOROFORM-d) δ: 3.84 (br. s., 2H), 2.97 (t, J=12.1 Hz, 2H),2.38-2.47 (m, 2H), 2.17-2.24 (m, 2H), 2.15 (s, 3H), 2.04 (s, 3H),1.39-1.51 (m, 9H).

Step D:tert-butyl-4-acetoxy-4-(3,3-difluorobutyl)piperidine-1-carboxylate (16E)

To a solution oftert-butyl-4-acetoxy-4-(3-oxobutyl)piperidine-1-carboxylate (2.66 g, 8.5mmol,) in CH₂Cl₂ (15 mL) was added DAST (4.5 mL, 34 mmol) and theresulting mixture was stirred for 24 h room temperature. A saturatedaqueous NaHCO₃ solution was added and the resulting biphasic mixture wasstirred vigorously for 15 min. The two layers were separated and theaqueous phase was extracted with CH₂Cl₂. The combined organic phase weredried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography on silica gel to give the title compound 16E (1.27g).

Step E:tert-butyl-4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carboxylate (16F)

To a solution oftert-butyl-4-acetoxy-4-(3,3-difluorobutyl)piperidine-1-carboxylate (100mg, 0.426 mmol) in MeOH (10 mL) and H₂O (2 mL) was added NaOH (145 mg,8.45 mmol). The resulting mixture was stirred at 40° C. for 4 h. Aftercooling to room temperature, the mixture was acidified with 2N HClsolution. After removal of MeOH, the resulting solution was extractedwith ethyl acetate. The organic layer was dried over Na₂SO₄, filtered,and evaporated to dryness under reduced pressure to give the crudeproduct which was used in the next step without further purification.

Step F: 4-(3,3-difluorobutyl)piperidin-4-ol (16G)

The solution oftert-butyl-4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carboxylate(0.932 g, 3.2 mmol) in the solution of HCl in 1,4-dioxane (3M, 5 mL) wasstirred at room temperature for 1 hour. The solution was evaporated todryness under reduced pressure to give the product which was used in thenext step without further purification. LC-MS: m/z 194.3 (M+H)⁺.

General Procedure 17

Step A:tert-butyl-4-hydroxy-4-(2-(trifluoromethyl)allyl)piperidine-1-carboxylate(17B)

A solution of tert-butyl 4-oxopiperidine-1-carboxylate (500 mg, 2.51mmol) and allylbromide (1.2 g, 6.3 mol, 2.5 eq.) in THF (5 mL) andsaturated ammonium chloride solution (20 mL) was cooled to 10° C., andzinc dust (328 mg, 5.0 mol, 2 eq.) was added portion wise. After theaddition was complete, the reaction mixture was stirred at roomtemperature overnight, when TLC (heptane/EtOAc 7:1) indicated completeconversion. The reaction mixture was diluted with water (5 mL), and thenextracted with EtOAc. The organic layer was washed with saturated NaHCO₃solution, brine, and evaporated to give the title compound, which wasused in the next step without further purification.

Step B: 4-(2-(trifluoromethyl)allyl)piperidin-4-ol (17C)

To a solution oftert-butyl-4-hydroxy-4-(2-(trifluoromethyl)allyl)piperidine-1-carboxylate17B (300 mg, 0.97 mmol), in DCM (5 mL) was added a solution of HCl indioxane (3 M, 1 mL, 3 mmol), and then the mixture was stirred at roomtemperature for 16 hrs. The mixture was concentrated in vacuo to get thedesired compound which was used directly for the next step. LC-MS: m/z210.2 (M+H)⁺

Step C: 4-(3,3,3-trifluoro-2-methylpropyl)piperidin-4-ol (17D)

To a mixture oftert-butyl-4-hydroxy-4-(2-(trifluoromethyl)allyl)piperidine-1-carboxylate(100 mg, 0.32 mmol) in EtOH (5 mL) was added 10% Pd/C (20 mg) and a dropof AcOH. The mixture was stirred at 40° C. for 16 hrs under H₂atmosphere. The reaction mixture was filtered through a celite pad; thefiltrate was concentrated to get the title compound which was useddirectly for the next step without purification. LC-MS: m/z 212.2 (M+H)⁺

General Procedure 18

Step A:

Compound 18B (1 eq.) was taken in dry THF and cooled to −78° C. when asolution of n-Butyllithium (1.2 eq.) in hexane was added over a periodof 15 min at −78° C. under nitrogen atmosphere. The reaction mixture wasstirred for 30 min −78° C., and then allowed to stir at −5° C. for 30min. The resulting mixture was then cooled again to −78° C., andtert-butyl 4-oxopiperidine-1-carboxylate (18A, 0.9 eq.) in THF was addedover a period of 15 min. The resulting reaction mixture was then allowedto warm up to room temperature and stirred at r.t. for 16 hrs. Theprogress of the reaction was monitored by TLC. Upon completion ofreaction, the mixture was quenched with satd. NH₄Cl solution (500 mL)and extracted with EtOAc. The combined organic layers were washed withwater, dried over Na₂SO₄ and concentrated under reduced pressure. Thecrude product was purified by column chromatography using silica gel(100-200 mesh) and 10% EtOAc in hexane to afford the correspondingcompounds 18C-1, 18C-2 and 18C-3 as light yellow oils. tert-butyl4-hydroxy-4-(pyridin-2-ylmethyl)piperidine-1-carboxylate (18C-1)

¹H NMR (CHLOROFORM-d) δ: 8.49-8.48 (m, 1H), 7.64 (t, 1H, J=8 Hz), 7.18(t, 1H, J=8 Hz), 7.12 (d, 1H, J=7.6 Hz), 3.80-3.77 (m, 2H), 3.24-3.22(m, 2H), 2.90 (s, 2H), 1.54-1.47 (m, 4H), 1.45 (s, 9H).

tert-butyl4-hydroxy-4-((6-methylpyridin-2-yl)methyl)piperidine-1-carboxylate(18C-2)

¹H NMR (CHLOROFORM-d) δ: 7.51 (t, 1H, J=7.6 Hz), 7.02 (d, 1H, J=7.6 Hz),6.90 (d, 1H, J=7.6 Hz), 6.36 (bs, 1H), 3.79-3.77 (m, 2H), 3.24-3.22 (m,2H), 2.84 (s, 2H), 2.51 (s, 3H), 1.51-1.47 (m, 4H), 1.45 (s, 9H).

tert-butyl4-((6-fluoropyridin-2-yl)methyl)-4-hydroxypiperidine-1-carboxylate(18C-3)

¹H NMR (CHLOROFORM-d) δ: 7.76-7.70 (m, 1H), 7.02 (d, 1H, J=7.2 Hz), 6.82(d, 1H, J=8 Hz), 4.44 (s, 1H), 3.80-3.78 (m, 2H), 3.21-3.20 (m, 2H),2.87 (s, 2H), 1.63-1.49 (m, 4H), 1.45 (s, 9H).

Step B:

Compound 18C (1 eq.) was dissolved in DCM, cooled to 0° C., and TFA (10eq.) was added at 0° C. and the reaction mixture was then stirred for3-4 hrs at room temperature until LCMS and TLC confirmed completion ofthe reaction. The reaction mixture was concentrated to dryness,triturated 3 to 4 times with DCM and washed with n-pentane to affordcompound 18D as colorless oil. The crude product was used for the nextstep directly without further purification.

General Procedure 19

Step A: The corresponding 2-R-3-methylpyridine (1 eq.) was taken in dryTHF and cooled to −78° C. A solution of lithium diisopropylamide (1.8eq.) 2.5M in THF was added to the above reaction mixture over 15 min at−78° C. under nitrogen atmosphere and stirred for 30 min at sametemperature. The reaction mixture was then stirred at −5° C. for 30 minbefore cooling it again to −78° C. when tert-butyl4-oxopiperidine-1-carboxylate (19A, 0.9 eq.) in THF was added over 15min. The resulting mixture was then allowed to stir at room temperaturefor 16 hrs. The progress of the reaction was monitored by TLC. Uponcompletion of reaction, the mixture was quenched with satd. NH₄Clsolution (500 mL) and extracted with EtOAc. The combined organic layerswas washed with water, dried over Na₂SO₄ and concentrated under reducedpressure. The crude product was purified by column chromatography usingsilica gel (100-200 mesh) and 10% EtOAc in Hexane to afford the titlecompound 19B as light yellow oil. tert-butyl4-hydroxy-4-(pyridin-3-ylmethyl)piperidine-1-carboxylate (19B-1)

¹H NMR (CHLOROFORM-d) δ: 8.51-8.46 (m, 2H), 7.56 (d, 1H, J=8 Hz),7.27-7.24 (m, 1H), 3.88-3.81 (m, 2H), 3.12-3.07 (m, 2H), 2.76 (s, 2H),1.63-1.61 (m, 2H), 1.49-1.47 (m, 2H), 1.45 (s, 9H).

Step B: compound 19B-1 or 19B-2 (1 eq.) was dissolved in DCM, cooled to0° C. to which TFA (10 eq.) was added at 0° C. and the reaction mixturewas then stirred for 3-4 hrs at room temperature until LCMS and TLCconfirmed completion of the reaction. The reaction mixture wasconcentrated to dryness, triturated 3 to 4 times with DCM and washedwith n-pentane to afford compound 19C-1 or 19C-2, respectively, ascolorless oil. The crude product was used for the next step withoutpurification.

General Procedure 20

Step A: 2-fluoroquinoline (20B)

To a solution of 2-chloroquinoline (4.9 g, 30 mmol) in 200 mL ofanhydrous DMSO was added cesium fluoride (9.13 g, 60 mmol), and theresulting mixture was stirred at 130° C. overnight, when LC-MS showedcompletion of the reaction. After cooling, the reaction mixture wasdiluted with water, and then extracted with ethyl acetate. The organiclayer was then washed with brine, dried over anhy. Na₂SO₄, andconcentrated in vacuo. Column chromatography (6% EtOAc/PE) afforded 3.34g of title compound. ¹H NMR (CHLOROFORM-d) δ: 8.23 (d, J=8.6 Hz, 1H),7.89 (d, J=8.6 Hz, 1H), 7.82-7.86 (m, 1H), 7.67 (d, J=8.5, 7.0, 1.5 Hz,1H), 7.47-7.53 (m, 1H), 7.35 (d, J=8.6 Hz, 1H). LC-MS: m/z 148.2 (M+H)⁺

Step B: 2-fluoroquinoline-8-sulfonyl chloride (20C)

A solution of 2-fluoroquinoline (1.3 g, 8.9 mmol) in chlorosulfonic acid(15 mL) was stirred at −5-0° C. for 15 minutes and at 130° C. overnight.The resulting reaction mixture was poured into an ice-water mixture (300mL), stirred at room temperature for 20 min, and extracted with EtOAc.The organic layer was then washed with brine, dried over Na₂SO₄ andsolvent was removed. The residue was purified by column chromatographyusing a gradient elution from 100% PE to PE/EtOAc (100:6) to afford 1.1g of title compound. ¹H NMR (CHLOROFORM-d) δ: 8.56 (d, J=7.5 Hz, 1H),8.43 (t, J=8.3 Hz, 1H), 8.25 (d, J=8.3 Hz, 1H), 7.72 (t, J=7.8 Hz, 1H),7.32 (dd, J=8.9, 3.0 Hz, 1H). LC-MS: m/z 246.3 (M+H)⁺

General Procedure 21

Step A: 3-fluoroquinoline (21B)

Quinolin-3-amine (4 g, 27.7 mmol) was added to HBF₄ (26 mL, 48% aqueoussolution) portionwise at room temperature, and the mixture was stirredat room temperature until it became homogeneous. The mixture was thencooled to 0° C., and a solution of NaNO₂ (2.4 g, 34.8 mmol) in H₂O (8mL) was added dropwise, when the reaction mixture became heterogeneous.The mixture was stirred at 0° C. for 1 hour, then the mixture wasfiltered, and the filtered cake was washed with cold EtOH, then Et₂O.The resulting solid was dried under vacuum, then suspended in toluene ina round bottom flask and was refluxed for 1.5 hours. The resultingmixture was cooled to room temperature, and then poured into cold water.The organic layer was dried over Na₂SO₄, and then concentrated in vacuoto obtain the desired product (1.6 g). LC-MS: m/z 148.1 (M+H)⁺

Step B: 3-fluoroquinoline-8-sulfonyl chloride (21C)

A mixture of 3-fluoroquinoline (0.6 g, 4.08 mmol) and HSO₃Cl (2 mL) in around bottom flask equipped with a cooling condenser was stirred at 130°C. overnight. When TLC indicated that the reaction was complete, theresulting mixture was carefully poured into crushed ice, the mixture wasextracted with DCM (100 mL×3), and the combined organic layers weredried over Na₂SO₄, and concentrated. The crude mixture was purified bychromatography (5% Ethyl Acetate/PE) to give the desired3-fluoroquinoline-8-sulfonyl chloride. ¹H NMR (CHLOROFORM-d) δ: 9.15 (d,J=2.6 Hz, 1H), 8.53 (d, J=7.6 Hz, 1H), 8.23 (dd, J=8.2, 0.9 Hz, 1H),7.97 (dd, J=8.1, 2.8 Hz, 1H), 7.69-7.83 (m, 1H). LC-MS: m/z 246.7 (M+H)⁺

General Procedure 22

Step A: 5-fluoroquinoline (22A)

To a solution of quinolin-5-amine (2 g, 13.9 mmol) in 10 mL of 48% HBF₄at 0° C. was added sodium nitrite (933 mg, 13.5 mmol) portionwise. Thiswas stirred for 1 hour and then poured into 1:1 ethyl acetate diethylether mixture (50 mL). The resulting suspension was filtered and thesolid was dried. This solid was added portionwise to refluxing xylene(30 mL) and stirred for 3 hours, then allowed to cool. The xylene wasdecanted off and the residue was dissolved in 1N HCl (50 mL). Afterneutralization with NaHCO₃, the mixture was extracted with ethyl acetate(3×50 mL). The extracts were dried over sodium sulfate, filtered and thevolatiles were removed under reduced pressure. The residue was purifiedby silica gel chromatography (3% EtOAc/PE) to afford 800 mg of titlecompound as colorless oil. LC-MS: m/z 148.2 (M+H)⁺

Step B: 5-fluoroquinoline-8-sulfonyl chloride (22C)

5-fluoroquinoline (800 mg, 5.4 mmol) was added slowly to 10 mL ofchlorosulfonic acid at 0° C. When the addition was complete, thereaction mixture was heated at 130° C. overnight. The solution wasallowed to cool and was slowly poured over ice. The aqueous layer wasextracted with ethyl acetate (3×50 mL). The combined organic extractswere dried and evaporated to give the crude product, which was purifiedby column chromatography (5% EtOAc/PE) to afford 400 mg of titlecompound. ¹H NMR (CHLOROFORM-d) δ: 7.40 (t, J=8.46 Hz, 1H), 7.74 (dd,J=8.60, 4.30 Hz, 1H), 8.55-8.64 (m, 2H), 9.32 (dd, J=4.30, 1.88 Hz, 1H).LC-MS: m/z 4 246 (M+H)⁺

General Procedure 23

Step A: 6-fluoro-8-nitroquinoline (23B)

A mixture of 6-fluoroquinoline (2 g, 13.6 mmol) and fuming HNO₃ (15 mL)in a round bottom flask equipped with a cooling condenser was refluxedfor 100 hours, the resulting mixture was cooled to r.t., poured slowlyinto crushed ice/H₂O, and then the mixture was extracted with DCM (200mL×3). The combined organic layers were dried over Na₂SO₄, andconcentrated. The residue was passed through a short pad of silica gelto give 1.6 g of title compound. ¹H NMR (CHLOROFORM-d) δ: 9.08 (dd,J=4.1, 1.5 Hz, 1H), 8.25 (dd, J=8.5, 1.5 Hz, 1H), 7.89 (dd, J=7.5, 2.8Hz, 1H), 7.72 (dd, J=8.1, 2.8 Hz, 1H), 7.62 (dd, J=8.4, 4.3 Hz, 1H).LC-MS: m/z 466.6 (M+H)⁺

Step B: 6-fluoroquinolin-8-amine (23C)

To a mixture of 6-fluoro-8-nitroquinoline (1.6 g, 8.3 mmol), and NH₄Cl(2 g, 41.5 mmol) in EtOH/H₂O (10 mL/10 mL) in a round bottom flaskequipped with a refluxing condenser was added Zn (5.4 g, 16.6 mmol) dustin portions at room temperature, and the resulting mixture was stirredat 60° C. overnight. The reaction mixture was filtered, and the filtratewas extracted with EtOAc. The combined organic layers were dried overNa₂SO₄, and concentrated to give 1.0 g of crude product, which was useddirectly for the next step without further purification. LC-MS: m/z163.2 (M+H)⁺

Step C: 6-fluoroquinoline-8-sulfonyl chloride (23D)

(a) Thionyl chloride (2.1 mL) was added dropwise to water (12.5 mL) at5° C. This mixture was allowed to warm to room temperature and stirredovernight. CuCl (10 mg) was then added and the resulting yellow solutionwas cooled to 0° C.(b) Concentrated hydrochloric acid (6.75 mL) was cooled to 0° C. while6-fluoroquinolin-8-amine (1 g) was added portionwise. The mixture wasallowed to warm up slightly between additions, during which time thereaction mixture turned yellow. After the addition was complete, thereaction mixture was cooled to −5° C. and a solution of NaNO₂ (0.5 g) inwater (2 mL) was added dropwise. After complete addition and at −5° C.,the resulting mixture was added slowly to the cooled thionylchloride/CuCI mixture from part (a). Then the mixture was stirred at 0°C. for about 1 hour. The resulting mixture was extracted with DCM,combined organic layers were dried over Na₂SO₄, concentrated to yield500 mg of title compound which was used for the next step withoutfurther purification. LC-MS: m/z 246.7 (M+H)⁺

General Procedure 24-1

Step A: Benzo[d]thiazole-4-sulfonyl chloride (24B)

Benzo[d]thiazole (1 g, 7.45 mol) was added dropwise to chlorosulfonicacid (5.5 mmol) at 0° C. After the addition was complete, the mixturewas stirred at room temperature for 0.5 h and then heated at 105° C. andstirred overnight. The resulting mixture was cooled to −10° C. andquenched by pouring on crushed ice slowly. The resulting mixture wasextracted with EtOAc (100 mL×2). The combined organic phase was washedwith brine, dried over anhy. Na₂SO₄ and concentrated in vacuo. Columnchromatography (15% PE/EtOAc) afforded 218 mg of title compound. ¹H NMR(CHLOROFORM-d) δ: 9.41 (s, 1H), 8.41 (dd, J=8.1, 1.0 Hz, 1H), 8.29 (dd,J=7.7, 1.1 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H). LC-MS: m/z 234.7 (M+H)⁺

General Procedure 24

Step A: benzo[c]isothiazole (24B)

To a solution of o-toluidine (10 g, 93.4 mmol) in 50 mL toluene wasadded SOCl₂ (12.1 g, 102 mmol) dropwise at 0° C. After the addition wascomplete, the reaction mixture was heated to reflux and stirredovernight. The reaction mixture was cooled to room temperature, andconcentrated under reduced pressure to give a yellow oil. The oil wasdissolved in toluene (100 mL), then a solution ofN-sulfinylmethanesulfonamide (20.6 g, 146 mmol) was added dropwise,followed by pyridine (7.3 g, 93.4 mmol). The mixture was heated toreflux and stirred at that temperature overnight. Toluene was thenremoved under reduced pressure, the residue was dissolved in EtOAc (200mL) and washed with water (2×200 mL). The organic layer was washed withbrine, dried and evaporated to give the crude product. The crude productwas purified by column chromatography (3% EtOAc/PE) to afford 6.2 gtitle compound as colorless oil. ¹H NMR (CHLOROFORM-d) δ 9.22 (s, 1H),7.88 (d, J=9.7 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.46 (ddd, J=8.9, 6.5,1.2 Hz, 1H), 7.26 (dd, J=7.9, 6.6 Hz, 1H).

Step B: benzo[c]isothiazole-7-sulfonyl chloride (24C)

Benzo[c]isothiazole 24B (1 g, 7.45 mmol) was added dropwise tochlorosulfonic acid (5.5 mmol) at 0° C. After the addition was complete,the mixture was stirred at room temperature for 0.5 h and then heated at105° C. and stirred overnight. The resulting mixture was cooled to −10°C. and quenched by pouring on crushed ice slowly. The resulting mixturewas extracted with EtOAc (100 mL×2). The combined organic phase waswashed with brine, dried over anhy. Na₂SO₄ and concentrated in vacuo.Column chromatography (15% PE/EtOAc) afforded 200 mg of title compound.¹H NMR (CHLOROFORM-d) δ: 9.68 (s, 1H), 8.66 (d, J=1.9 Hz, 1H), 8.10 (d,J=9.4 Hz, 1H), 7.99 (dd, J=9.4, 2.1 Hz, 1H).

General Procedure 25

Step A: 1-fluoro-3-nitro-2-thiocyanatobenzene (25B)

A solution of 2-fluoro-6-nitroaniline (3 g, 0.02 mol) in conc. sulphuricacid (30 mL) and water (30 mL) was diazotized at 0-3° C. for 90 min withaqueous sodium nitrite (1.45 g, 0.021 mol). After addition of potassiumthiocyanate (2.522 g, 0.026 mol) in water (10 mL), the diazo-liquor wasstirred vigorously into a suspension of cuprous thiocyanate (6.05 g,0.05 mol) in water (20 mL) at 5° C. After stirring at 5° C. for 2 hr,the mixture was then heated at 70° C. for 20 min, then was cooledovernight, filtered, and the cake extracted with EtOAc to get the crudeproduct (3.96 g) which was used in the next step without furtherpurification. LC-MS: m/z 199.2 (M+H)⁺

Step B: 7-fluorobenzo[d]thiazol-2-amine (25C)

A mixture of 1-fluoro-3-nitro-2-thiocyanatobenzene 2 (3.96 g, 0.02 mol),ethanol (30 mL), water (25 mL) and conc. hydrochloric acid (25 mL) wasrefluxed gently during the addition of hydrogen-reduced iron powder (8g). After refluxing for 16 hr, the liquor was filtered hot, cooled, theresidue filtered, dissolved in hot water, and neutralized with ammoniaand then extracted with EtOAc to get the compound7-fluorobenzo[d]thiazol-2-amine (1 g) as a colorless oil. LC-MS: m/z169.2 (M+H)⁺

Step C: 7-fluorobenzo[d]thiazole (25D)

To a solution of 7-fluorobenzo[d]thiazol-2-amine 25C (1 g, 5.95 mmol) inTHF (10 mL) was added isoamyl nitrite (1.51 g, 12.9 mmol) at roomtemperature. After refluxing for 3 hr, the reaction mixture was thenallowed to cool to room temperature and poured into ice water (50 mL),and then extracted with EtOAc. The organic extract was washed with waterand brine, dried and evaporated. The residue was chromatographed onsilica gel to get the 7-fluorobenzo[d]thiazole as colorless oil. LC-MS:m/z 154.2 (M+H)⁺

Step D: 7-fluorobenzo[d]thiazole-4-sulfonyl chloride (25E)

7-fluorobenzo[d]thiazole 25D (500 mg, 3.26 mmol) was added dropwise tochlorosulfonic acid (2.5 mmol) at 0° C. After the addition was complete,the mixture was stirred at room temperature for 0.5 h and then heated at105° C. and stirred overnight. The resulting mixture was cooled to −10°C. and quenched by pouring on crushed ice slowly. The resulting mixturewas extracted with EtOAc (20 mL×2). The combined organic phase waswashed with brine, dried over anhy. Na₂SO₄ and concentrated in vacuo.Column chromatography (15% PE/EtOAc) afforded 200 mg of title compound.¹H NMR (CHLOROFORM-d) δ: 9.44 (s, 1H), 8.32 (dd, J=8.6, 4.6 Hz, 1H),7.38 (t, J=8.5 Hz, 1H).

General Procedure 26

Step A: 2-amino-6-fluorobenzo[d]thiazole-4-sulfonyl chloride (26B)

6-fluorobenzo[d]thiazol-2-amine (1 g, 5.95 mol) was added dropwise tochlorosulfonic acid (5.0 mmol) at 0° C. After the addition was complete,the mixture was stirred at room temperature for 0.5 h and then heated at105° C. and stirred overnight. The resulting mixture was cooled to −10°C. and quenched by pouring on crushed ice slowly. The resulting mixturewas extracted with EtOAc (100 mL×2). The combined organic phase waswashed with brine, dried over anhy. Na₂SO₄ and concentrated in vacuo.Column chromatography (50% PE/EtOAc) afforded 200 mg of title compound.LC-MS: m/z 266.7 (M+H)⁺

Step B: ethyl 4-(2-amino-6-fluorobenzo[d]thiazole-4-sulfonamido)benzoate(26C)

To a solution of the ethyl 4-aminobenzoate (413 mg, 2.5 mmol) in 20 mLof DCM was added pyridine (600 mg, 7.5 mmol) and2-amino-6-fluorobenzo[d]thiazole-4-sulfonyl chloride (668 mg, 2.5 mmol).The resulting mixture was stirred at 50° C. overnight. After removal ofDCM, the residue was partitioned between water and EtOAc. The organiclayer was washed with 2 N HCl, water and brine, dried over Na₂SO₄ andconcentrated to give crude product, which was purified by chromatographyto give pure compound 26C. ¹H NMR (CHLOROFORM-d) δ: 8.10 (s, 1H),7.93-7.82 (m, 2H), 7.59 (dd, J=8.2, 2.6 Hz, 1H), 7.47 (dd, J=7.5, 2.6Hz, 1H), 7.20-7.09 (m, 2H), 5.73 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 1.35(t, J=7.1 Hz, 3H). LC-MS: m/z 396.5 (M+H)⁺

General Procedure 27

Step A: 6-chloro-N-methylbenzo[d]thiazol-2-amine (27B)

To a solution of 2,6-dichlorobenzo[d]thiazole (2 g, 10 mmol) in 10 mLTHF was added 25% MeNH₂ in water (3 mL) dropwise. After the additioncomplete, the reaction mixture was stirred at room temperatureovernight. Filter off the product and washed with methanol. Drying invacuo to yield 1.5 g of the desired compound. LC-MS: m/z 204.2 (M+H)⁺

Step B: 6-chloro-2-(methylamino)benzo[d]thiazole-4-sulfonyl chloride(27C)

A solution of 6-chloro-N-methylbenzo[d]thiazol-2-amine (500 mg, 2.53mmol) in chlorosulfonic acid (5 mL) was stirred at 130° c. overnight.The solution was allowed to cool and slowly added to a large excess ofice. The aqueous layer was extracted with EtOAc (3×50 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified bychromotography (silica gel) eluting with PE/EA=1:1 to get the titlecompound. ¹H NMR (CHLOROFORM-d) δ: 7.95 (d, J=1.9 Hz, 1H), 7.89 (d,J=2.1 Hz, 1H), 6.70 (br. s., 1H), 3.16 (d, J=4.3 Hz, 3H). LC-MS: m/z 297(M+H)⁺

General Procedure 28

Step A: quinazolin-4-ol (28B)

A solution of ethyl 2-aminobenzoate (5.0 g, 30 mmol) in methoxyethanol(20 mL) was treated with formamidine acetate (8 g, 77 mmol) under refluxfor 17 h. A second portion of formamidine acetate (8 g, 77 mmol) wasthen added, and the reflux was continued for 7 more hours. The mixturewas cooled, and the solvent was removed under vacuum. The residue wastaken in saturated NaHCO₃ and extracted with ethyl acetate. The organiclayers were combined, washed with saturated NaHCO₃, and dried withmagnesium sulfate, and the solvent was removed under vacuum to give thedesired compound (4.84 g, 91%), which was used for the next step withoutfurther purification. LC-MS: m/z 147.7 (M+H)⁺

Step B: 4-hydroxyquinazoline-8-sulfonyl chloride (28C)

Chlorosulfonic acid (4.10 mL, 62.6 mmol) was slowly added toquinazolin-4-ol (1.09 g, 0.26 mmol). The resulting mixture was heated to140° C. and stirred for 3 hours at the same temperature. After coolingto room temperature, the reaction mixture was poured into crushed ice.The mixture was extracted with DCM (100 mL×3), the combined organiclayers were dried over Na₂SO₄, filtered, and the filtrate wasconcentrated in vacuo. The residue was purified via flash chromatography(5% PE: Ethyl Acetate) to give 370 mg of 4-hydroxyquinazoline-8-sulfonylchloride. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.76 (t, J=7.79 Hz, 1H) 8.26(ddd, J=9.67, 7.92, 1.48 Hz, 2H) 9.02 (s, 1H). LC-MS: m/z 245.7 (M+H)⁺

General Procedure 29

Step A: methyl 2-(difluoromethoxy)-4-nitrobenzoate (29B)

A mixture of methyl 2-hydroxy-4-nitrobenzoate (1.1 g, 5.6 mmol), sodium2-chloro-2,2-difluoroacetate (1.0 g, 6.6 mmol) and Na₂CO₃ (710 mg, 6.7mmol) in DMF (10 mL) was stirred at 100° C. overnight. After cooling tort, the mixture was partitioned between water and EtOAc. The organiclayer was separated and washed with twice with water, then brine, driedover Na₂SO₄ and concentrated, and purified by a standard method to givethe title product (330 mg). ¹H NMR (CHLOROFORM-d) δ: 8.15-8.19 (m, 1H),8.13 (s, 1H), 8.06 (d, J=8.6 Hz, 1H), 6.68 (s, 1H), 3.98 (t, J=72.8 Hz,1H).

Step B: Methyl 4-amino-2-(difluoromethoxy)benzoate (29C)

A mixture of methyl 2-(difluoromethoxy)-4-nitrobenzoate (330 mg, 1.3mmol) and 10% Pd on carbon (50 mg) in THF (10 mL) was stirred at roomtemperature under hydrogen atmosphere for 6 hours. The solid was removedby filtration and the solvent was concentrated to give the crudeaniline. LC-MS: m/z 218.1 (M+H)⁺

General Procedure 30

Step A: methyl 2-chloro-4-nitrobenzoate (30B)

To a solution of 2-chloro-4-nitrobenzoic acid (10 g, 0.06 mol) in MeOH(120 mL) was added H₂SO₄ (5 mL). The resulting mixture was stirred at60° C. overnight. After cooling to room temperature, the mixture wasbrought to pH=8 using sodium bicarbonate solution. After removal ofMeOH, the resulting crude mixture was purified by column chromatography(20% CH₂Cl₂/PE) to afford 4 g of the title compound. LC-MS: m/z 216.6(M+H)⁺

Step B: methyl 2-cyano-4-nitrobenzoate (30C)

A mixture of methyl 2-chloro-4-nitrobenzoate (2 g, 9.3 mmol), CuCN (3.3g, 37.2 mmol), and Pd(PPh₃)₄ (1.075 g, 0.93 mmol) was suspended in DMF(15 mL) and then subjected to microwave irradiation at 150° C. for 4hours. After the mixture was concentrated under reduced pressure, theresidue was partitioned between ethyl acetate and water. The organiclayer was dried over Na₂SO₄, filtered, and the filtrate was evaporatedto dryness under reduced pressure. The crude material was purified bycolumn chromatography (20% EA/PE) to afford 0.9 g of title compound.LC-MS: m/z 207.1 (M+H)⁺.

Step C: methyl 4-amino-2-cyanobenzoate (30D)

To a solution of methyl 2-cyano-4-nitrobenzoate (0.9 g, 4.4 mmol) inMeOH (5 mL) was added Pd/C (0.1 g). The resulting mixture was stirred atroom temperature for 2 hours under hydrogen atmosphere. The mixture wasfiltered, and the filtrate was evaporated to dryness under reducedpressure to give the title product (0.77 g), which was used in the nextstep without further purification. LC-MS: m/z 177.2 (M+H)⁺

General Procedure 31

Step A: 6-methyl-5-nitropicolinonitrile (31B)

To a mixture of methyl 2-bromo-4-nitrobenzoate (31A, 4 g, 18.4 mmol) in10 mL DMA was added CuCN (6.6 g, 74 mmol), and Pd(PPh₃)₄ (1.06 g, 0.92mmol) under N₂. The mixture was stirred at 150° C. under microwaveirradiation for 4 hrs. Then the mixture was diluted water and filtered.The filtrate was extracted with EtOAc (20 mL). The organic layer wasdried, concentrated, and purified by silica gel chromatography (PE:EtOAc=3:1) to give 500 mg the title compound. ¹H NMR (CHLOROFORM-d) δ:8.08 (d, J=7.9 Hz, 1H), 7.68 (d, J=7.9 Hz, 1H), 2.85 (s, 3H).

Step B: 6-methyl-5-nitropicolinic acid (31C)

To a solution of 6-methyl-5-nitropicolinonitrile (31B, 500 mg, 3.1 mmol)in 2-propanol (1 mL) and water (5 mL) was added potassium tert-butoxide(687 mg, 6.13 mmol). The mixture was stirred at 100° C. overnight, whenLCMS indicated that the reaction was complete. The mixture diluted withwater, and then extracted with DCM (10 mL×3). The aqueous phase wasacidified with 1N HCl solution, and extracted with DCM. The organiclayer was dried and concentrated to give the crude product which wasused to the next step without further purification. LC-MS: m/z 181(M−H)⁺

Step C: 5-amino-6-methylpicolinic acid (31D)

To a solution of 6-methyl-5-nitropicolinic acid (31C, 500 mg, 2.75 mmol)in methanol (10 ml) was added Pd/C (50 mg). The solution was stirred atr.t. under H₂ atmosphere for 1 h, when LC-MS showed that s.m. wasconsumed. Then the mixture was filtered and concentrated to give thecrude product which was used to the next step without furtherpurification. LC-MS: m/z 153(M+H)⁺

Step D: methyl 5-amino-6-methylpicolinate (31E)

To a solution of 5-amino-6-methylpicolinic acid (31D, 240 mg, 1.5 mmol)in methanol was added conc. H₂SO₄. The solution was stirred at 60° C.overnight, when LC-MS showed that s.m. was consumed. Then the mixturewas concentrated and neutralized with Na₂CO₃ solution to pH=7. Themixture was extracted with DCM (10 mL×3). The organic layer was driedand concentrated to give the title compound 31E. LC-MS: m/z 167 (M+H)⁺

General Procedure 36

Step A:

To a solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (36A,1.24 g, 4.0 mmol) in anhydrous THF (50 mL) was added LDA solution (2.1mL, 5.2 mmol) dropwise at −65° C. for 30 min, and the resulting mixturewas stirred at −65° C. for 15 min, and then stirred at −30° C. foranother 30 min. After the addition of RBr (4.8 mmol, 1.2 eq) at −65° C.,the mixture was stirred for another 15 min at −65° C., and then it wasallowed to warm up to r.t. for 2 hrs. The reaction was quenched byadding 50 mL NH₄Cl solution (1 M), the organic phase was concentratedand the crude product purified by a standard method to give the titlecompound 36B.

Step B:

A mixture of the corresponding compound 36B (2.0 mol) and HCl (10 mL, 4Msolution in 1,4-dioxane) was stirred at r.t. for 4 hrs. The solvent wasthen removed, and the residue was dissolved in 3.0 mL NaOH solution and2.0 mL of methanol. The mixture was stirred under microwave irradiationat 110° C. for 10 min and then concentrated. The residue was purified bya standard method to give the title compound 36C.

Step C:

To a vial was added compound 36C (24.36 mmol) in 10 mL THF, thenborane-tetrahydrofuran complex (3.3 mL, 32.88 mmol) was added, and themixture was heated at reflux for 3 h. After washing with satd. NaHCO₃,brine, the combined organic layer was dried over anhy. Na₂SO₄ andconcentrated in vacuo to get the crude product 36D and 36E, which wasused directly for the next step without purification.

Step D:

To a round-bottomed flask was added compound 36E (or 36B-1 or 36D-1, or36D-2, or 36D-3) (0.2 mmol, 1 eq.), DMF (5 mL), DIPEA (0.6 mmol, 3.0eq.), HBTU (2.4 mmol, 1.2 eq.), and Intermediate 36G (e.g.,Ar-8-quinoline) (0.2 mmol, 1.0 eq.) sequentially. The reaction mixturewas stirred at room temperature overnight or until TLC showed that s.m.was consumed. The mixture was diluted with brine, extracted with ethylacetate, the organic layer was dried with anhydrous Na₂SO₄, filtered,and the filtrate was concentrated in vacuo. The desired product 36F waspurified by a standard method.

Compound 149 General Procedure 36, Step DN-(4-(4-benzyl-4-(hydroxymethyl)piperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (400 MHz, CDCl₃) δ: 9.17 (dd, J=4.4, 1.7 Hz, 1H), 8.52 (dd,J=8.4, 1.6 Hz, 1H), 8.43 (dd, J=7.3, 1.3 Hz, 1H), 8.26-8.19 (m, 1H),7.78-7.65 (m, 2H), 7.29-7.15 (m, 10H), 4.17-4.06 (m, 1H), 3.75 (s, 1H),3.60 (t, J=5.7 Hz, 2H), 2.74 (s, 2H), 2.08-2.01 (m, 1H), 1.64-1.60 (m,3H), 1.48-1.38 (m, 2H). LC-MS: m/z 516.6 (M+H)

Compound 250 General Procedure 36, Step D Ethyl4-isobutyl-1-(4-(quinoline-8-sulfonamido)benzoyl)piperidine-4-carboxylate

¹H NMR (CHLOROFORM-d) δ: 9.16 (dd, J=4.3, 1.6 Hz, 1H), 8.38 (dd, J=7.3,1.1 Hz, 1H), 8.32 (dd, J=8.3, 1.6 Hz, 1H), 8.06 (dd, J=8.3, 1.1 Hz, 1H),7.59-7.67 (m, 2H), 7.13-7.19 (m, J=8.6 Hz, 2H), 7.04-7.11 (m, J=8.6 Hz,2H), 4.17 (q, J=7.0 Hz, 2H), 3.51 (br. s., 1H), 3.10 (br. s., 1H), 2.93(br. s., 1H), 2.15-2.24 (m, 1H), 2.08 (d, J=10.2 Hz, 1H), 1.61-1.74 (m,4H), 1.47 (d, J=12.9 Hz, 2H), 1.29-1.36 (m, 2H), 1.26 (s, 1H), 0.83-0.91(m, 6H). LC-MS: m/z 524.7 (M+H)⁺

Compound 137 General Procedure 36, Step DN-(4-(4-formyl-4-isobutylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.50 (s, 1H), 9.16 (dd, J=4.3, 1.3 Hz, 1H),8.27-8.41 (m, 2H), 8.02-8.11 (m, 1H), 7.55-7.68 (m, 2H), 7.12-7.19 (m,J=8.3 Hz, 2H), 7.05-7.11 (m, J=8.6 Hz, 2H), 3.48 (s, 1H), 2.93-3.17 (m,2H), 1.96 (br. s., 2H), 1.64 (tt, J=13.1, 6.5 Hz, 1H), 1.48 (br. s.,3H), 1.22-1.42 (m, 2H), 0.82-0.94 (m, 6H). LC-MS: m/z 480.7 (M+H)⁺

Compound 172 General Procedure 36, Step DN-(4-(4-(hydroxymethyl)-4-isobutylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.17 (dd, J=4.3, 1.6 Hz, 1H), 8.27-8.42 (m,2H), 8.06 (dd, J=8.1, 1.3 Hz, 1H), 7.58-7.67 (m, 2H), 7.13-7.21 (m, 2H),7.05-7.12 (m, 2H), 3.54 (s, 3H), 3.30 (br. s., 2H), 1.69 (dd, J=12.6,6.2 Hz, 2H), 1.47 (d, J=11.6 Hz, 3H), 1.34 (d, J=5.4 Hz, 3H), 0.95 (d,J=6.7 Hz, 6H). LC-MS: m/z 482.7 (M+H)⁺

Compound 238 General Procedure 36, Step D(N-(4-(4-(hydroxymethyl)-4-phenylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14 (dd, J=4.3, 1.6 Hz, 1H), 8.36 (dd, J=7.4,1.2 Hz, 1H), 8.31 (dd, J=8.5, 1.5 Hz, 1H), 8.02-8.07 (m, 1H), 7.57-7.65(m, 2H), 7.36-7.42 (m, 2H), 7.30-7.34 (m, 2H), 7.23-7.28 (m, 1H),7.11-7.16 (m, J=8.6 Hz, 2H), 7.04-7.09 (m, J=8.6 Hz, 2H), 3.53 (s, 2H),3.06-3.16 (m, 2H), 2.16-2.30 (m, 1H), 2.10-2.16 (m, 1H), 1.71-1.91 (m,3H), 1.67 (dt, J=5.7, 2.9 Hz, 1H). LC-MS: m/z 502.7 (M+H)⁺

Compound 216 General Procedure 36, Step DN-(4-(4-(hydroxymethyl)-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.49 (s, 1H), 8.34 (dd, J=8.2, 0.9 Hz, 1H),8.12 (dd, J=7.7, 0.9 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.19 (s, 4H), 4.62(s, 1H), 3.71 (br. s., 1H), 3.58 (br. s., 1H), 3.47 (s, 2H), 1.75 (s,1H), 1.59 (br. s., 1H), 1.42-1.51 (m, 2H), 1.35 (d, J=5.1 Hz, 3H), 1.31(br. s., 2H), 0.95 (d, J=6.7 Hz, 6H) LC-MS: m/z 488.7 (M+H)⁺

Compound 219 General Procedure 36, Step DN-(4-(4-(hydroxymethyl)-4-isobutylpiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.11 (d, J=1.9 Hz, 1H), 9.02 (d, J=1.9 Hz, 1H),8.50 (dd, J=7.5, 1.3 Hz, 1H), 8.31 (dd, J=8.3, 1.3 Hz, 1H), 7.91 (dd,J=8.5, 7.4 Hz, 1H), 7.14-7.24 (m, 4H), 3.70 (br. s., 1H), 3.57 (br. s.,1H), 3.46 (s, 2H), 3.37 (s, 1H), 3.28 (br. s., 2H), 1.66-1.77 (m, 1H),1.55 (br. s., 1H), 1.43 (br. s., 2H), 1.24-1.37 (m, 3H), 0.95 (s, 3H),0.93 (s, 3H). LC-MS: m/z 483.6 (M+H)⁺

General Procedure 37

Step A: tert-butyl4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate(37C)

To a solution of tert-butyldimethyl(prop-2-yn-1-yloxy)silane (0.5 mL,2.46 mmol) in 30 mL of anhydrous THF was added dropwise n-BuLi (1.2 mL,2.95 mmol) at −78° C. under N₂. After stirring for 1 h at −78° C.,tert-butyl 4-oxopiperidine-1-carboxylate (588.4 mg, 2.95 mmol) in THF (2mL) was added dropwise to the above solution at −78° C. under N₂. Theresulting mixture was stirred at −78° C. under N₂ for 2 h, then allowedto warm to r.t. and stirred for another 1.5 h. The reaction mixture wascooled to −78° C. and quenched by sat. NH₄Cl aq., and the resultingmixture was extracted with EtOAc (50 mL, 30 mL). The combined organicphase was washed with brine, dried over anhy. Na₂SO₄ and concentrated invacuo to afford 1.10 g of title compound. LC-MS: m/z 370.7 (M+H)⁺. ¹HNMR (CHLOROFORM-d) δ: 4.37 (s, 2H), 3.74 (d, J=6.2 Hz, 2H), 3.35-3.24(m, 2H), 2.46 (t, J=6.2 Hz, 1H), 1.92-1.84 (m, 2H), 1.71 (ddd, J=12.9,9.1, 3.8 Hz, 2H), 1.47 (s, 9H), 0.92 (s, 9H), 0.13 (s, 6H).

Step B:tert-butyl-4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-((methoxycarbonyl)oxy)piperidine-1-carboxylate (37D)

To a solution of tert-butyl4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate(500 mg, 1.353 mmol) in 30 mL of anhydrous THF was added dropwise n-BuLi(0.65 mL, 1.623 mmol) at −78° C. under N₂. After stirring for 1 h at−78° C., methyl carbonochloridate (176.2 mg, 1.623 mmol) in THF (1 mL)was added dropwise to the above solution at −78° C. under N₂. Theresulting mixture was stirred at −78° C. under N₂ for 2 h, then allowedto warm to r.t. and stirred for another 8 h. The reaction mixture wascooled to −78° C. and quenched by sat. NH₄Cl aq., and the resultingmixture was extracted with EtOAc (50 mL, 30 mL). The combined organicphase was washed with brine, dried over anhy. Na₂SO₄ and concentrated invacuo. Column chromatography (15% PE/EtOAc) afforded 453 mg of titlecompound. ¹H NMR (CHLOROFORM-d) δ: 4.40 (s, 2H), 4.26-4.15 (m, 2H),3.80-3.67 (m, 2H), 3.41-3.28 (m, 2H), 2.27-2.14 (m, 2H), 2.00 (ddd,J=13.1, 9.2, 3.9 Hz, 2H), 1.48 (s, 9H), 1.33 (t, J=7.1 Hz, 4H), 0.92 (s,9H), 0.14 (s, 6H).

Step C: tert-butyl4-(3-hydroxyprop-1-yn-1-yl)-4-((methoxycarbonyl)oxy)piperidine-1-carboxylate(37E)

To a solution of tert-butyl4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-4-((methoxycarbonyl)oxy)piperidine-1-carboxylate(450 mg, 1.02 mmol) in 30 mL of anhydrous THF was added TBAF (800.5 mg,3.06 mmol) at 0° C. under N₂. After stirring for 1 h at 0° C., thereaction mixture was quenched by sat. NH₄Cl aq., and the resultingmixture was extracted with EtOAc (50 mL, 30 mL). The combined organicphase was washed with brine, dried over anhy. Na₂SO₄ and concentrated invacuo. Column chromatography (15% PE/EtOAc) afforded 290 mg of titlecompound. MS (ES) M+H expected 313.25. found 313.47. ¹H NMR(CHLOROFORM-d) δ: 4.36 (s, 2H), 4.21 (q, J=7.1 Hz, 2H), 3.80-3.70 (m,2H), 3.41-3.29 (m, 2H), 2.24-2.13 (m, 2H), 2.00 (ddd, J=13.2, 9.3, 3.9Hz, 2H), 1.95 (s, 1H), 1.48 (s, 9H), 1.34 (t, J=7.1 Hz, 3H).

Step D: tert-butyl4-((methoxycarbonyl)oxy)-4-(3-oxoprop-1-yn-1-yl)piperidine-1-carboxylate(37F)

To a solution of tert-butyl4-(3-hydroxyprop-1-yn-1-yl)-4-((methoxycarbonyl)oxy)piperidine-1-carboxylate (130 mg, 0.398 mmol) in 30 mL of DCM was addedNaHCO₃ (334 mg, 3.98 mmol), DMP (338 mg. 0.796 mmol) at r.t. Thereaction mixture was stirred at r.t. for 8 h. The reaction mixture wasfiltered and the residue mixture was extracted with EtOAc (50 mL, 30mL). The combined organic phase was washed with brine, dried over anhy.Na₂SO₄ and concentrated in vacuo. Column chromatography (15% PE/EtOAc)afforded 110 mg of title compound. ¹H NMR (CHLOROFORM-d) δ: 9.29 (s,1H), 4.25 (q, J=7.1 Hz, 2H), 3.80-3.64 (m, 2H), 3.49-3.35 (m, 2H),2.30-2.18 (m, 2H), 2.17-2.03 (m, 2H), 1.48 (s, 9H), 1.36 (t, J=7.1 Hz,3H).

Step E: tert-butyl4-(3,3-difluoroprop-1-yn-1-yl)-4-((methoxycarbonyl)oxy)piperidine-1-carboxylate(37G)

To a solution of tert-butyl4-((methoxycarbonyl)oxy)-4-(3-oxoprop-1-yn-1-yl)piperidine-1-carboxylate(60 mg, 0.1846 mmol) in 5 mL of DCM was added DAST (89.3 mg, 0.5583mmol) at 0° C. under N₂. After stirring for 8 h at r.t., the reactionmixture was quenched by sat. NH₄Cl aq., and the resulting mixture wasextracted with DCM (50 mL, 30 mL). The combined organic phase was washedwith brine, dried over anhy. Na₂SO₄ and concentrated in vacuo. Columnchromatography (15% PE/EtOAc) afforded 63 mg of title compound. ¹H NMR(CHLOROFORM-d) δ: 6.27 (t, J=54.4 Hz, 1H), 4.30-4.18 (m, 2H), 3.75 (d,J=7.0 Hz, 2H), 3.46-3.28 (m, 2H), 2.32-2.14 (m, 2H), 2.10-1.99 (m, 2H),1.48 (s, 9H), 1.35 (t, J=7.1 Hz, 3H).

Step F: tert-butyl4-(3,3-difluoroprop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate (37H)

To a solution of tert-butyl4-(3,3-difluoroprop-1-yn-1-yl)-4-((methoxycarbonyl)oxy)piperidine-1-carboxylate (6.0 g, 18.5 mmol) in 100 mL of MeOH and 15 mLof water was added K₂CO₃ (3.822 g, 27.7 mmol) at r.t. The reactionmixture was stirred at 48° C. for 3 h. The reaction mixture was cooledto r.t., and was extracted with EtOAc (150 mL, 100 mL). The combinedorganic phase was washed with brine, dried over anhy. Na₂SO₄ andconcentrated in vacuo. Column chromatography (15% PE/EtOAc) afforded4.81 g of title compound.

Step G: tert-butyl4-(3,3-difluoropropyl)-4-hydroxypiperidine-1-carboxylate (37I)

A solution of tert-butyl4-(3,3-difluoroprop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate (350mg, 1.273 mmol) in 30 mL of anhydrous THF was stirred with Pd/C (200 mg)under H₂ atmosphere at 15 psi at 48° C. for 8 h. The reaction mixturewas cooled to r.t. and filtered, and the resulting mixture wasconcentrated in vacuo to afforded 293 mg of title compound. ¹H NMR(CHLOROFORM-d) δ: 5.89 (tt, J=56.9, 4.3 Hz, 1H), 3.84 (dd, J=9.8, 3.5Hz, 2H), 3.24-3.10 (m, 2H), 2.05-1.89 (m, 2H), 1.67-1.60 (m, 2H), 1.55(m, 4H), 1.47 (s, 9H).

Step H: 4-(3,3-difluoropropyl)piperidin-4-ol (37J)

A solution of tert-butyl4-(3,3-difluoropropyl)-4-hydroxypiperidine-1-carboxylate (293 mg, 1.075mmol) in 5 mL of 3.5 N HCl in dioxane was stirred at r.t. for 30 min.The reaction mixture was concentrated in vacuo to give 301 mg of thetitle product which was used in the next step directly.

Step I:

To a solution of the corresponding (aryl-sulfonamido)benzoic acid (1.05mmol) in 15 mL of DMF was added HBTU (479 mg, 1.26 mmol), DIPEA (203 mg,1.58 mmol) and 4-(3,3-difluoropropyl)piperidin-4-ol (226.3 mg, 1.05mmol), sequentially at room temperature. The reaction mixture wasstirred at room temperature for 1 hour. The mixture was poured intowater and extracted with EtOAc (50 mL) twice. The combined organic layerwas washed with brine and dried over anhy. Na₂SO₄. The combined organiclayer was concentrated in vacuo. The title compound was purified by astandard method.

Compound 204N-(4-(4-(3,3-difluoropropyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 10.41 (s, 1H), 9.13 (dd, J=4.2, 1.7 Hz, 1H),8.52 (dd, J=8.4, 1.7 Hz, 1H), 8.42 (dd, J=7.3, 1.3 Hz, 1H), 8.36-8.24(m, 1H), 7.80-7.64 (m, 2H), 7.11 (q, J=8.7 Hz, 4H), 6.06 (td, J=59.4,55.3 Hz, 1H), 4.44 (m, 1H), 4.16-3.92 (m, 1H), 3.16-2.91 (m, 2H), 1.84(dqt, J=19.9, 13.0, 6.6 Hz, 2H), 1.51-1.40 (m, 3H), 1.40-1.29 (m, 3H).LC-MS: m/z 490.68 (M+H)⁺

Compound 235N-(4-(4-(3,3-difluoropropyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 10.76 (s, 1H), 9.66 (s, 1H), 8.50 (dd, J=8.1,1.0 Hz, 1H), 8.11 (dd, J=7.6, 1.0 Hz, 1H), 7.65 (t, J=7.9 Hz, 1H), 7.17(d, J=8.7 Hz, 2H), 7.10 (d, J=8.7 Hz, 2H), 6.06 (tt, J=57.1, 4.3 Hz,1H), 4.10 (d, J=5.3 Hz, 1H), 3.11 (dd, J=51.3, 35.5 Hz, 3H), 1.83 (dd,J=18.4, 11.9 Hz, 2H), 1.55-1.28 (m, 6H). LC-MS: m/z 496.59 (M+H)⁺

Compound 230N-(4-(4-(3,3-difluoropropyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 10.65 (s, 1H), 9.13 (dd, J=13.1, 1.8 Hz, 2H),8.50 (dd, J=7.4, 1.3 Hz, 1H), 8.37 (dd, J=8.4, 1.2 Hz, 1H), 8.05-7.93(m, 1H), 7.12 (dd, J=25.5, 8.7 Hz, 4H), 6.06 (tt, J=57.1, 4.2 Hz, 1H),4.10-3.93 (m, 1H), 3.04 (m, 3H), 1.84 (m, 2H), 1.54-1.27 (m, 6H). LC-MS:m/z 491.58 (M+H)⁺

General Procedure 38

Step A: (E)-tert-butyl4-(3,3-difluoroprop-1-enyl)-4-hydroxypiperidine-1-carboxylate (38B)

To a solution of tert-butyl4-(3,3-difluoroprop-1-yn-1-yl)-4-hydroxypiperidine-1-carboxylate (280mg, 1.016 mmol) in 30 mL of anhydrous THF was added dropwise sodiumdihydro-bis-(2-methoxyethoxy)aluminate (587 mg, 2.032 mmol, 70%) at −78°C. under N₂. After the addition, the reaction mixture was stirred at−78° C. under N₂ for 5 h. The reaction mixture was quenched by sat.NH₄Cl aq., and the resulting mixture was extracted with EtOAc (50 mL, 30mL). The combined organic phase was washed with brine, dried over anhy.Na₂SO₄ and concentrated in vacuo to afford 291 mg of title compound. MS(ES) M+H expected 278.15. found 178.30. ¹H NMR (CHLOROFORM-d) δ:6.29-6.08 (m, 2H), 6.01-5.84 (m, 1H), 3.98-3.84 (m, 2H), 3.20 (t, J=11.4Hz, 2H), 1.76-1.62 (m, 4H), 1.48 (s, 9H).

Step B: (E)-4-(3,3-difluoroprop-1-enyl)piperidin-4-ol (38C)

A solution of (E)-tert-butyl4-(3,3-difluoroprop-1-enyl)-4-hydroxypiperidine-1-carboxylate (38C) (293mg, 1.075 mmol) in 5 mL of 3.5 N HCl in dioxane was stirred at r.t. for30 min. The reaction mixture was concentrated in vacuo to give 300 mg ofthe title product as a yellow liquid which was used in the next stepdirectly.

General Procedure 39

Step A: N,N′-disulfinyl-3-fluoro-1,2-diaminobenzene (39B)

To a solution of 3-fluorobenzene-1,2-diamine (7.9 g, 62.7 mmol) in 80 mLof pyridine was added dropwise SOCl₂ (16 mL) at 0° C. The reactionmixture was stirred at 100° C. for 8 hours. The mixture was poured intowater and extracted with EtOAc (50 mL) twice. The combined organic layerwas washed with brine and dried over anhy. Na₂SO₄. The combined organiclayer was concentrated in vacuo. Column chromatography (15%Petroleum/EtOAc) afforded 11.5 g of title compound.

Step B: 7-fluorobenzo[c][1,2,5]thiadiazole-4-sulfonyl chloride (39C)

A solution of N,N′-disulfinyl-3-fluoro-1,2-diaminobenzene 39B (11.5 g,52.75 mmol) in 80 mL of chlorosulfonic acid was heated at 110° C. for 8hours. The mixture was cooled to r.t. and poured into water andextracted with EtOAc (50 mL) twice. The combined organic layer waswashed with brine and dried over anhy. Na₂SO₄. The combined organiclayer was concentrated in vacuo. Column chromatography (15%Petroleum/EtOAc) afforded 7.1 g of title compound. ¹H NMR (CHLOROFORM-d)δ: 8.48 (dd, J=8.4 Hz, 4.4 Hz, 1H), 7.45 (t, J=8.4 Hz, 1H). LC-MS: m/z253.2 (M+H)⁺.

Step C: Ethyl4-(7-fluorobenzo[c][1,2,5]thiadiazole-4-sulfonamido)benzoate (39D)

To a solution of ethyl 4-aminobenzoate (412 mg, 2.5 mmol) in 20 mL ofDCM was added pyridine (600 mg, 7.5 mmol) and7-fluorobenzo[c][1,2,5]thiadiazole-4-sulfonyl chloride (39C) (633 mg,2.5 mmol). The resulting mixture was stirred at 50° C. overnight. Afterremoval of DCM, the residue was partitioned between water and EtOAc. Theorganic layer was washed with 2 N HCl, water and brine, dried overNa₂SO₄ and concentrated to give crude product 39D, which was confirmedby LCMS, and used in the next reaction without further purification. ¹HNMR (CHLOROFORM-d) δ: 8.33 (dd, J=8.0, 4.6 Hz, 1H), 7.85 (d, J=8.7 Hz,2H), 7.66 (s, 1H), 7.35-7.30 (m, 1H), 7.12 (d, J=8.7 Hz, 2H), 4.31 (q,J=7.1 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H). LC-MS: m/z 382.4 (M+H)⁺.

Step D: ethyl 4-(2,3-diamino-4-fluorophenylsulfonamido)benzoate (39E)

To a solution of the compound 39D (382 mg, 1.0 mmol) in AcOH/H₂O (8 mL/3mL) at 70° C. was added zinc powder (975 mg, 15 mmol) and the resultingsuspension was stirred at 70° C. for 1 h. The solid was filtered off andwashed with EtOAc. The filtrate was partitioned between satd. NaHCO₃ andEtOAc. The organic layer was separated and washed with water and brine,dried over anhydrous Na₂SO₄ and concentrated to give crude product 39E,which was confirmed by LCMS, and used in the next reaction withoutfurther purification. LC-MS: m/z 354.4 (M+H)⁺.

Step E: 4-(2,3-diamino-4-fluorophenylsulfonamido)benzoic acid (39F)

To a solution of the compound 39E (350 mg, 1 mmol) in EtOH/H₂O (10 mL/3mL) was added LiOH.H₂O (200 mg, 5 mmol) and the resulting suspension wasstirred at 70° C. overnight. The solvent was concentrated and theresidue was partitioned between aqueous 2 N HCl and EtOAc. The organiclayer was separated and washed with water and brine, dried over Na₂SO₄and concentrated to give the desired crude product 39F, which wasconfirmed by LCMS, and used in subsequent reaction without furtherpurification. LC-MS: m/z 326.3 (M+H)⁺.

Step F

To a solution of compound 39F (0.2 mmol) and in DCM (10 mL) was addedHBTU (91 mg, 0.24 mmol) and stirred at r.t. for 20 min, then thecorresponding compound 7 (0.2 mmol) and DIPEA (0.6 mmol) were added.After stirring for 30 mins, the reaction was partitioned between satd.Na₂CO₃ solution and DCM. The organic layer was separated and washed withwater and brine, dried over Na₂SO₄ and concentrated, and then purifiedby a standard method to give title product 39G.

Compound 2562,3-diamino-N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-4-fluorobenzenesulfonamide

¹H NMR (CHLOROFORM-d) δ: 10.56 (s, 1H), 7.81 (dd, J=7.9, 1.6 Hz, 1H),7.42-7.33 (m, 2H), 7.27 (m, 3H), 7.08 (d, J=8.6 Hz, 2H), 6.99 (dd,J=9.0, 5.9 Hz, 1H), 6.46 (dd, J=9.2 Hz, 1H), 5.71 (s, 2H), 5.43 (s, 1H),4.87 (s, 2H), 4.35 (s, 1H), 3.45 (s, 2H), 3.12 (s, 1H), 1.78-1.12 (m,4H). LC-MS: m/z 519.70 (M+H)⁺

Compound 2542,3-diamino-4-fluoro-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzenesulfonamide

¹H NMR (CHLOROFORM-d) δ: 7.27 (d, J=8.5 Hz, 2H), 7.20 (dd, J=9.0, 5.9Hz, 1H), 7.15 (s, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.49 (t, J=9.1 Hz, 1H),4.38 (s, 1H), 3.44 (s, 2H), 3.25 (s, 1H), 1.85 (td, J=12.9, 6.5 Hz, 1H),1.67 (s, 4H), 1.44 (d, J=6.0 Hz, 2H), 1.00 (d, J=6.6 Hz, 6H). LC-MS: m/z465.66 (M+H)⁺

Step G

To a solution of the corresponding compound 39G (0.9 mmol) inethanol/water (30 mL/4 mL) was added 1,4-dioxane-2,3-diol (130 mg, 1.08mmol) and the resulting suspension was stirred at 30° C. overnight. Thesolvent was removed in vacuo and the residue was partitioned betweenwater and EtOAc. The organic layer was separated and washed with waterand brine, dried over Na₂SO₄ and concentrated, and then purified by astandard method to give title product 39H.

Compound 4448-fluoro-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.14 (d, J=8.8 Hz, 2H), 8.46 (dd, J=8.3, 5.2Hz, 1H), 7.88 (s, 1H), 7.54 (t, J=8.5 Hz, 1H), 7.20 (d, J=8.1 Hz, 2H),7.07 (d, J=8.1 Hz, 2H), 4.31 (s, 1H), 3.29 (s, 3H), 1.82 (td, J=12.9,6.5 Hz, 1H), 1.57 (s, 4H), 1.41 (d, J=6.0 Hz, 2H), 0.98 (d, J=6.6 Hz,6H). LC-MS: m/z 487.68 (M+H)⁺

Compound 234N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-8-fluoroquinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.15 (d, J=9.5 Hz, 2H), 8.47 (dd, J=8.3, 5.1Hz, 1H), 7.87 (s, 1H), 7.53 (dd, J=17.0, 8.5 Hz, 2H), 7.40 (d, J=7.6 Hz,1H), 7.31 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.2 Hz, 3H), 7.09 (d, J=7.2 Hz,2H), 4.61 (s, 1H), 3.58 (m, 2H), 3.32 (m, 1H), 2.38-2.01 (m, 4H). LC-MS:m/z 541.79 (M+H)⁺

General Procedure 40 Compound 202

Step A:

To a solution of2-amino-6-fluoro-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide(Compound 145) (200 mg, 0.4 mmol) in THF (5 mL) was added isoamylnitrite (94 mg, 0.8 mmol). The reaction mixture was stirred at 70° C.for 3 hrs under nitrogen atmosphere. After completion of the reaction(monitored by TLC), the reaction mixture was concentrated in vacuo. Theresidue was dissolved in water, and extracted with ethyl acetate (3×50mL). Combined organic extracts were washed with brine (20 mL), driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to obtain the crude product, which was purified by a standardmethod.

Compound 446:6-fluoro-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.26 (s, 1H), 7.89 (s, 1H), 7.88-7.84 (m, 2H),7.22 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 4.33 (s, 1H), 3.30 (s,3H), 1.90-1.79 (m, 1H), 1.52 (d, J=51.2 Hz, 4H), 1.42 (d, J=6.0 Hz, 2H),0.98 (d, J=6.6 Hz, 6H). LC-MS: m/z 492.68 (M+H)⁺

Compound 401 General Procedure 39, Started from Compound 154N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-6-fluorobenzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.26 (s, 1H), 7.89 (s, 1H), 7.87 (d, J=7.6 Hz,2H), 7.52 (dd, J=7.8, 1.7 Hz, 1H), 7.40 (dd, J=7.7, 1.6 Hz, 1H),7.34-7.29 (m, 1H), 7.25 (dd, J=10.0, 5.0 Hz, 3H), 7.13 (d, J=8.5 Hz,2H), 4.64 (s, 1H), 3.60 (s, 2H), 3.31 (s, 1H), 2.39-1.99 (m, 4H). LC-MS:m/z 546.7 (M+H)⁺

General Procedure 42

Step A: 6-chloroquinolin-2-amine (42B)

A mixture of 2,6-dichloroquinoline (500 mg, 2.5 mmol), acetamide (3 g,50.8 mmol) and K₂CO₃ (1.75 g, 12.7 mmol) in a round bottom flask wasstirred at 200° C. for 1.5 hours until TLC indicated that2,6-dichloroquinoline was consumed. The resulting mixture was cooled toroom temperature, and was partitioned between dichloromethane and H₂O,the organic layer was dried over anhydrous Na₂SO₄, concentrated, and theresidue was purified by a standard method to give 440 mg of the titlecompound. LCMS (m/z): 179.7 (M+1)⁺

Step B: 2-amino-6-chloroquinoline-8-sulfonyl chloride (42C)

6-chloroquinolin-2-amine (350 mg) was added to 5 mL of HClSO₃ at 0° C.in portions, and then the mixture was stirred at 100° C. for 1 hour. Theresulting mixture was cooled to room temperature, then it was pouredwith caution into crushed ice and H₂O, and the resulting mixture wasextracted with dichloromethane. The combined organic layers were driedover anhydrous Na₂SO₄, concentrated to provide the crude title compoundwhich was used in the next step without further purification. LCMS(m/z): 278.1 (M+1)⁺

Step C: 4-(2-amino-6-chloroquinoline-8-sulfonamido)benzoic acid (42D)

A mixture of 2-amino-6-chloroquinoline-8-sulfonyl chloride (500 mg, 1.8mmol), 4-aminobenzoic acid (300 mg, 2.2 mmol) and pyridine (1 mL) in 10mL of THF was stirred at 30° C. overnight, when LCMS indicated that thereaction was complete. The resulting mixture was concentrated, and theresidue was purified by a standard method to yield the title compound.LCMS (m/z): 378.8 (M+1)⁺

Step D: 4-(2-aminoquinoline-8-sulfonamido)benzoic acid (42E)

A mixture of 4-(2-amino-6-chloroquinoline-8-sulfonamido)benzoic acid(150 mg, 0.44 mmol), 10% Pd/C (20 mg) in methanol (5 mL) was stirredunder H₂ atmosphere overnight when LCMS indicated that the reaction wascomplete. The resulting mixture was filtered, and the filtrate wasconcentrated to yield 100 mg of title compound, which was used in thenext step without further purification. LCMS (m/z): 344.6 (M+1)⁺

Step E: Compound 402:2-amino-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinoline-8-sulfonamide

To a mixture of 4-isobutylpiperidin-4-ol (70 mg, 0.44 mmol),4-(2-aminoquinoline-8-sulfonamido)benzoic acid (100 mg, 0.44 mmol), andHBTU (134 mg, 0.53 mmol) in DCM (5 mL) was added DIPEA (1 mL) dropwiseat room temperature, and then the mixture was stirred at roomtemperature for 1 hour. The resulting mixture was concentrated, purifiedby a standard method to yield the title compound. ¹H NMR (CHLOROFORM-d)δ: 8.10-8.20 (m, 1H), 7.89 (d, J=9.1 Hz, 1H), 7.69-7.82 (m, 1H),7.06-7.26 (m, 5H), 6.80 (d, J=9.1 Hz, 1H), 5.41 (s, 2H), 4.33 (br. s.,1H), 3.41-3.19 (m., 3H), 1.82 (dt, J=12.9, 6.4 Hz, 1H), 1.63-1.46 (m,4H), 1.40 (d, J=5.9 Hz, 2H), 0.97 (d, J=6.7 Hz, 6H). LCMS (m/z): 483.7(M+1)⁺

General Procedure 43

Step A: Benzyl4-hydroxy-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (43B)

To a round-bottom flask containing Zn dust (2.3 g, 36 mmol) was addeddibromoethane (585 mg, 3.11 mmol). The resulting mixture was warmed to60° C. and allowed to cool for 1 min. This heating-cooling process wasrepeated three more times, and then the flask was allowed to cool for anadditional 3 min. Trimethylsilylchloride (456 mg, 4.2 mmol) in THF (5mL) was added, followed by addition of ethyl-2-bromoacetate (2 g, 12mmol) in THF (8 mL). The reaction was warmed to 60° C. for an additionaltwo hours until a dark grey suspension was obtained. The mixture wascooled to room temperature; benzyl 4-oxopiperidine-1-carboxylate (1.9 g,8.2 mmol) in THF (20 mL) was then added. The resulting mixture wasstirred for 3 days, and then quenched with water. The solid was filteredoff, and the aqueous was extracted with ethyl acetate. The combinedorganic layers were washed with brine and dried over Na₂SO₄.Purification by a standard method gave the desired product. ¹H NMR(CHLOROFORM-d) δ: 7.33-7.43 (m, 5H), 5.14 (s, 2H), 3.89-4.05 (m, 2H),3.68-3.79 (m, 3H), 3.22-3.36 (m, 2H), 2.49 (s, 2H), 2.19 (s, 1H), 1.71(d, J=12.6 Hz, 2H), 1.53 (dd, J=12.5, 4.2 Hz, 2H). LCMS (m/z): 308.1(M+1)⁺

Step B: benzyl4-(benzyloxymethoxy)-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate(43C)

A solution of compound 43B (0.5 g, 1.63 mmol) and diisopropylethylamine(1.26 g, 9.8 mmol) in CH₂Cl₂ (10 mL) was treated with benzylchloromethylether (636 mg 4.1 mmol) and stirred at room temperature for16 h. Purification a standard method gave the desired product. ¹H NMR(CHLOROFORM-d) δ: 7.30-7.44 (m, 9H), 5.15 (s, 2H), 4.92 (s, 2H), 4.69(s, 2H), 3.91 (br. s., 2H), 3.65 (s, 3H), 3.29 (br. s., 2H), 2.63 (s,2H), 2.20 (s, 1H), 2.02 (d, J=13.7 Hz, 2H), 1.69 (ddd, J=14.1, 11.7, 4.6Hz, 3H). LC-MS: m/z 428.6 (M+H)⁺

Step C: benzyl4-(benzyloxymethoxy)-4-(2-hydroxy-2-methylpropyl)piperidine-1-carboxylate(43D)

To a solution of benzyl 4-(benzyloxymethoxy)-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (500 mg, 1.17 mmol) in anhydrous THF (15 mL)was added dropwise a solution of methylmagnesium bromide (2 mL, 6 mmol)in diethyl ether at 0° C. After the addition was complete, the mixturewas stirred at room temperature for 1.5 h, and then cooled again in anice bath. Saturated ammonium chloride solution was added dropwise. Theresulting precipitate was dissolved by the addition of water (30 mL).The mixture was extracted three times with EtOAc. The combined organiclayers were dried over Na₂SO₄ and evaporated to get the crude productwhich was used directly for next step without further purification. LCMS(m/z): 428.2 (M+1)⁺

Step D: benzyl4-(benzyloxymethoxy)-4-(2-fluoro-2-methylpropyl)piperidine-1-carboxylate(43E)

To a solution of(4-hydroxy-4-(isothiazol-4-yl)piperidin-1-yl)(4-((quinolin-8-ylsulfonyl)methyl)phenyl)methanone(500 mg, 1.17 mmol) in DCM (10 mL) was added dropwise DAST (282 mg, 1.75mmol) while cooling on an ice-water bath. The mixture was allowed towarm up from 0° C. to room temperature, and was stirred for 16 hrs. Thereaction was quenched by dropwise addition of saturated ammoniumchloride solution, then was washed with saturated NaHCO₃ and extractedwith EtOAc. The organic layer was washed with brine, and thenconcentrated to get the crude product. Purification by a standard methodgave the desired product. ¹H NMR (CHLOROFORM-d) δ: 7.30-7.59 (m, 10H),5.15 (s, 2H), 4.85 (s, 2H), 4.71 (s, 2H), 3.83 (br. s., 2H), 3.38 (br.s., 2H), 1.91-2.05 (m, 3H), 1.59-1.70 (m, 2H), 1.47 (s, 3H), 1.42 (s,3H), 1.36 (s, 1H).

Step E: 4-(2-fluoro-2-methylpropyl)piperidin-4-ol (43F)

To a round bottom flask was addedbenzyl-4-(benzyloxymethoxy)-4-(2-fluoro-2-methylpropyl)piperidine-1-carboxylate(50 mg, 0.12 mmol), Pd/C (20 mg), and methanol (5 mL). The mixture wasstirred at room temperature for 16 hrs under hydrogen atmosphere. Thereaction mixture was filtered to get a solution, which was concentratedto give the desired product. The crude product was used directly for thenext step. LC-MS: m/z 176.2 (M+H)⁺

Step F: Compound 403:N-(4-(4-(2-fluoro-2-methylpropyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

To a round-bottom flask was added with 4-(2-fluoro-2-methylpropyl)piperidin-4-ol (25 mg 0.143 mmol),4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (47 mg, 0.143 mmol),DIPEA (110 mg, 0.85 mmol), HATU (54 mg, 0.143 mmol), and DCM (5 mL). Themixture was stirred at r.t. for 16 hours. After washing with satd.NaHCO₃, brine, the combined organic layer was dried over anhy. Na₂SO₄and concentrated in vacuo. Purification by a standard method gave thedesired compound. ¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (dd,J=8.1, 0.8 Hz, 1H), 8.10 (dd, J=7.5, 1.1 Hz, 1H), 7.93 (s, 1H), 7.54 (t,J=7.9 Hz, 1H), 7.16-7.23 (m, J=8.3 Hz, 2H), 7.05-7.15 (m, J=8.3 Hz, 2H),4.19-4.47 (m, 1H), 3.46 (d, J=15.6 Hz, 1H), 3.35 (d, J=15.3 Hz, 2H),1.89 (s, 3H), 1.84 (s, 3H), 1.49-1.55 (m, 3H), 1.46 (s, 3H). LC-MS: m/z492.65 (M+H)⁺

General Procedure 44

Step A: tert-butyl 4-acetoxy-4-allylpiperidine-1-carboxylate (44B)

A solution of tert-butyl 4-allyl-4-hydroxypiperidine-1-carboxylate (3.7g, 14.51 mmol) in dichloromethane (20 mL) was treated withdimethylaminopyridine (1.8 g, 14.51 mmol), acetic anhydride (4.1 mL,43.53 mmol) and triethylamine (6.1 mL, 43.53 mmol), and was stirredovernight at 20° C. The solvent was removed under reduced pressure andthe residue was partitioned between water and ethyl acetate. The aqueouslayer was extracted twice with ethyl acetate. Combined organic extractswere washed with water, dried (Na₂SO₄) and filtered. The filtrate wasconcentrated under reduced pressure, and purified by a standard methodto provide the title compound 44B (3.4 g). LC-MS: m/z 284.4 (M+H)⁺

Step B: (E)-tert-butyl4-acetoxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carboxylate (44C)

A flame-dried vial equipped with a magnetic stir bar was charged withTogni reagent (2.0 g, 7.0 mmol) and CuI (34 mg, 0.35 mmol), and wassealed with a septum. The vial was evacuated and backfilled with N₂ forthree times. MeOH (8 mL) and tert-butyl4-acetoxy-4-allylpiperidine-1-carboxylate (4.5 g, 14 mmol) were thenadded via syringe. The vial was kept at 80° C. for 2 h. The reactionmixture was concentrated in vacuo and the crude residue was purified bya standard method to afford the product (2.1 g). NMR (400 MHz,CHLOROFORM-d) δ: 1.47 (s, 9H), 1.66-1.77 (m, 2H), 2.00-2.07 (m, 3H),2.22 (d, J=13.43 Hz, 2H), 2.85 (qdd, J=10.61, 10.61, 10.61, 7.25, 1.21Hz, 2H), 3.11 (t, J=11.82 Hz, 2H), 3.81 (br. s., 2H), 5.58 (dt, J=15.98,7.19 Hz, 1H), 6.05 (d, J=16.12 Hz, 1H).

Step C: (E)-tert-butyl4-hydroxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carboxylate (44D)

To a mixture of (E)-tert-butyl4-acetoxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carboxylate (200 mg,0.57 mmol) in methanol (5 mL) was added 2M NaOH (2 mL, 4 mmol), themixture was held stirring at r.t. for 16 hrs, when TLC (20% EA/PE)indicated completion of the reaction. The mixture was concentrated invacuo, the residue was diluted with brine and extracted with EtOAc, andthe organic layer was concentrated in vacuo to get the crude product,which was used directly for the next step.

Step D: (E)-4-(4,4,4-trifluorobut-1-enyl)piperidin-4-ol (44E)

A solution of (E)-tert-butyl4-hydroxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carboxylate (200 mg,0.65 mmol) in 3M HCl/1,4-dioxane (5 mL) was stirred at room temperaturefor 2 hours. The solution was evaporated to dryness under reducedpressure to give the product which was used in the next step withoutfurther purification. LC-MS: m/z 210.2 (M+H)⁺.

Step E: Compound 404:(E)-N-(4-(4-hydroxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

To a round-bottom flask was added with(E)-4-(4,4,4-trifluorobut-1-enyl)piperidin-4-ol (50 mg 0.24 mmol),4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (80 mg, 0.24 mmol), DIPEA(155 mg, 1.2 mmol), HATU (110 mg, 0.29 mmol), and DCM (5 mL). Themixture was stirred at r.t. for 16 hours. After washing with brine, thecombined organic layer was dried over anhy. Na₂SO₄ and concentrated invacuo. Purification by a standard method gave the desired compound. ¹HNMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.10 (d,J=7.5 Hz, 1H), 7.99 (s, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.17-7.24 (m, J=8.3Hz, 2H), 7.08-7.15 (m, J=8.1 Hz, 2H), 5.78-5.94 (m, 1H), 5.64-5.76 (m,1H), 4.28-4.47 (m, 1H), 3.51 (s, 1H), 3.32-3.48 (m, 1H), 3.27 (br. s.,1H), 2.84 (dd, J=10.5, 7.0 Hz, 1H), 1.66 (br. s., 4H), 1.46 (d, J=9.7Hz, 2H). LC-MS: m/z 526.7 (M+H)⁺

General Procedure 45

Step A: tert-butyl4-((benzyloxy)methoxy)-4-(2-methylallyl)piperidine-1-carboxylate (45B)

To a solution of tert-butyl4-((benzyloxy)methoxy)-4-(2-methylallyl)piperidine-1-carboxylate (2.55g, 10.0 mmol) in dichloromethane (50 mL) was added BOMCl (3.12 g, 20.0mmol) and TEA (3.03 g, 30.0 mmol), and the mixture was stirred at 45° C.for 16 hrs. The solvent was then removed and the residue was purified bya standard method to obtain the desired product (3 g). LC-MS: m/z 376.6(M+H)⁺

Step B: tert-butyl4-((benzyloxy)methoxy)-4-(3-hydroxy-2-methylpropyl)piperidine-1-carboxylate(45C)

To a solution of tert-butyl4-((benzyloxy)methoxy)-4-(2-methylallyl)piperidine-1-carboxylate (3.05g, 8.1 mmol) in THF (50 mL) was added BH₃ solution in THF (32 mL, 1mol/L, 32.4 mmol), and the mixture was stirred at room temperature for16 hrs. Then 30% H₂O₂ solution (30 mL) and 10% sodium hydroxide solution(50 mL) were added slowly to the mixture, and the mixture was stirredfor another 2 hrs. The mixture was then treated with water (10 mL) andextracted with EtOAc (3×20 mL). The combined organic extracts were driedover Na₂SO₄ and the solvent was removed in vacuo. The residue waspurified by a standard method to give the product (1.97 g). LC-MS: m/z394.5 (M+H)⁺

Step C:tert-butyl-4-((benzyloxy)methoxy)-4-(2-methyl-3-oxopropyl)piperidine-1-carboxylate(45D)

A mixture oftert-butyl-4-((benzyloxy)methoxy)-4-(3-hydroxy-2-methylpropyl)piperidine-1-carboxylate(1.97 g, 5.0 mmol) and Dess-martin reagent (3.18 g) was stirred indichloromethane (60 mL) at r.t for 16 hrs. The reaction mixture wasquenched by adding 25% sodium bicarbonate solution (100 mL), then themixture was extracted by EtOAc (60 mL×2). The organic phase was combinedand concentrated to give a residue, which was further purified by astandard method to give the product (0.88 g). LC-MS: m/z 392.5 (M+H)⁺

Step D: tert-butyl4-((benzyloxy)methoxy)-4-(3,3-difluoro-2-methylpropyl)piperidine-1-carboxylate(45E)

A mixture of tert-butyl4-((benzyloxy)methoxy)-4-(2-methyl-3-oxopropyl)piperidine-1-carboxylate(0.88 g, 2.25 mmol) and DAST (0.8 g) in DCM (5 mL) was stirred at r.tfor 20 hrs. The reaction mixture was quenched by adding 25% sodiumbicarbonate solution (20 mL). The mixture was then extracted with DCMtwice. The organic phase was combined and concentrated to give aresidue, which was further purified by a standard method to obtain thetitle compound (0.33 g). LC-MS: m/z 414.5 (M+H)⁺

Step E: 4-(3,3-difluoro-2-methylpropyl)piperidin-4-ol (45F)

A mixture of tert-butyl4-((benzyloxy)methoxy)-4-(3,3-difluoro-2-methylpropyl)piperidine-1-carboxylate(0.33 g) and 5 M HCl in MeOH (4 mL) was stirred in methanol (15 mL) for3 hrs. The solvent was then removed under vacuum to obtain crude product(4-(3,3-difluoro-2-methylpropyl)piperidin-4-ol (0.11 g). LC-MS: m/z194.2 (M+H)⁺

Step F: Compound 405:N-(4-(4-(3,3-difluoro-2-methylpropyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

To a round-bottom flask was added4-(3,3-difluoro-2-methylpropyl)piperidin-4-ol (110 mg 0.57 mmol),4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (190 mg, 0.57 mmol),DIPEA (367 mg, 2.8 mmol), HATU (261 mg, 0.69 mmol), and DCM (5 mL). Themixture was stirred at r.t. for 16 hours. After washing with brine, thecombined organic layer was dried over anhy. Na₂SO₄ and concentrated invacuo. Purification by a standard method gave the desired compound. ¹HNMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.10 (d,J=7.5 Hz, 1H), 7.94 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.20 (d, J=8.5 Hz,2H), 7.12 (d, J=8.6 Hz, 2H), 5.90-5.61 (m, 1H), 4.36 (s, 1H), 3.57-3.42(m, 1H), 3.21 (s, 2H), 2.24 (d, J=7.6 Hz, 1H), 2.05 (s, 1H), 1.86-1.77(m, 2H), 1.36 (dd, J=14.8, 6.3 Hz, 4H), 1.10 (d, J=7.0 Hz, 3H). LC-MS:m/z 510.5 (M+H)⁺

General Procedure 46

Step A: Benzo[d]thiazole-4-sulfonyl chloride (46B)

Benzo[d]thiazole (1 g, 7.45 mol) was added dropwise to chlorosulfonicacid (5.5 mmol) at 0° C. After the addition was complete, the mixturewas stirred at room temperature for 0.5 h and then heated at 105° C. andstirred overnight. The resulting mixture was cooled to −10° C. andquenched by pouring on crushed ice slowly. The resulting mixture wasextracted with EtOAc (100 mL×2). The combined organic phase was washedwith brine, dried over anhy. Na₂SO₄ and concentrated in vacuo. Columnchromatography (15% PE/EtOAc) afforded 218 mg of title compound. ¹H NMR(CHLOROFORM-d) δ: 9.41 (s, 1H), 8.41 (dd, J=8.1, 1.0 Hz, 1H), 8.29 (dd,J=7.7, 1.1 Hz, 1H), 7.68 (t, J=7.9 Hz, 1H). LC-MS: m/z 234.7 (M+H)⁺

Step B: 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (46C)

To a solution of 4-aminobenzoic acid (10 g, 73 mmol) in DCM (100 mL) wasadded pyridine (29 g, 365 mmol), then aryl-sulfonyl chloride (20 g, 88mmol). The resulting mixture was heated at 40° C. for 16 hrs, when LC-MSshowed that the reaction was complete. The mixture was then filtered,and the filter cake was washed with Et₂O, and dried to afford titleproduct (23 g). ¹H NMR (DMSO-d₆) δ: 12.56 (br. s., 1H), 11.05 (s, 1H),9.63-9.68 (m, 1H), 8.51 (dd, J=8.1, 1.1 Hz, 1H), 8.12-8.18 (m, 1H), 7.70(d, J=8.6 Hz, 2H), 7.64-7.69 (m, 1H), 7.11-7.20 (m, 2H). LC-MS: m/z335.2 (M+H)⁺

Step C: 4-(2-amino-3-mercaptophenylsulfonamido)benzoic acid (46D)

To a solution of 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (500 mg,1.5 mmol) in 6 mL of EtOH was added hydrazine hydrate (479 mg, 15 mmol)at r.t. The reaction mixture was then stirred at 130° C. in microwavefor 1.5 h. The resulting mixture was then cooled, and partitionedbetween water and EtOAc. The organic phase was washed with brine, driedover anhy. Na₂SO₄ and concentrated in vacuo to afford the title compound(449.0 mg). LC-MS: m/z 323.4 (M+H)⁺

Step D: 4-(2-aminobenzo[d]thiazole-4-sulfonamido)benzoic acid (46E)

To a solution of 4-(2-amino-3-mercaptophenylsulfonamido)benzoic acid(671 mg, 2.07 mmol) in THF (15 mL) was added cyanic bromide (439.1 mg,4.14 mmol) at r.t. The reaction mixture was stirred at 80° C. for 8 h.The resulting mixture was then cooled, and partitioned between water andEtOAc. The organic phase was washed with brine, dried over anhy. Na₂SO₄and concentrated in vacuo to afford the title compound (730 mg). LC-MS:m/z 348.7 (M+H)⁴

Step E: Same procedure as General Procedure 2, Step C Compound 406:2-amino-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 7.93 (s, 1H), 7.82 (dd, J=7.8, 1.0 Hz, 1H),7.75 (dd, J=7.9, 1.0 Hz, 1H), 7.23 (d, J=8.5 Hz, 2H), 7.16 (t, J=7.6 Hz,1H), 7.13 (d, J=8.6 Hz, 2H), 5.71 (s, 2H), 4.36 (s, 1H), 3.47-3.19 (m,3H), 1.84 (dt, J=13.0, 6.4 Hz, 1H), 1.67 (s, 2H), 1.51 (s, 2H), 1.42 (d,J=6.0 Hz, 2H), 0.99 (d, J=6.6 Hz, 6H). LC-MS: m/z 489.70 (M+H)⁺

Compound 407:2-amino-N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 7.81 (d, J=7.9 Hz, 1H), 7.76 (dd, J=16.1, 7.8Hz, 2H), 7.38 (d, J=7.8 Hz, 1H), 7.33 (t, J=7.6 Hz, 1H), 7.30-7.19 (m,5H), 7.07 (t, J=7.8 Hz, 1H), 4.51 (d, J=13.9 Hz, 1H), 3.52 (d, J=16.0Hz, 2H), 2.84-2.72 (m, 1H), 2.68-2.56 (m, 1H), 1.72 (d, J=18.4 Hz, 1H),1.56 (d, J=15.3 Hz, 1H), 1.34 (d, J=14.7 Hz, 1H). LC-MS: m/z 543.67(M+H)⁺

General Procedure 47

Step A:

A solution of compound 47A (1.23 mol) in MeCN (10 mL) was mixed withwater (5 mL), CuCI (243 mg, 2.46 mmol), NaCl (500 mg) and 18-crown-6(0.5 mL). A solution of tert-butyl-nitrite (165 mg) was then addeddropwise with stirring, the solution was heated at reflux for 15 hrs.Then the resulting mixture was poured into water (20 mL), the aqueouslayer was extracted with EtOAc (3×50 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄ and evaporated to get thetitle compound. The crude product was used in the next step withoutfurther purification.

Step B:

To a solution of compound 47B (0.6 mmol) in THF (10 mL) was added 25%MeNH₂ in water (3 mL) dropwise. After the addition was complete, thereaction mixture was stirred at room temperature overnight. The crudeproduct was filtered off, washed with methanol, then dried thoroughlyand was then purified by a standard method to give the desired product.

Compound 408:N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)-2-(methylamino)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 8.33 (br. s., 1H), 7.77-7.84 (m, 1H), 7.70-7.77(m, 1H), 7.22 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 7.07-7.11 (m,1H), 6.25 (br. s., 1H), 4.35 (br. s., 1H), 3.44 (br. s., 1H), 3.36 (br.s., 1H), 3.22 (br. s., 1H), 3.13 (s, 3H), 1.83 (dd, J=12.9, 6.4 Hz, 2H),1.65 (br. s., 2H), 1.49 (br. s., 1H), 1.41 (d, J=5.9 Hz, 2H), 0.98 (d,J=6.7 Hz, 6H). LC-MS: m/z 503.6 (M+H)⁺

Compound 409:2-chloro-N-(4-(4-(2-chlorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 8.25 (br. s., 1H), 7.82 (d, J=7.8 Hz, 1H), 7.75(d, J=8.1 Hz, 1H), 7.52 (dd, J=7.7, 1.7 Hz, 1H), 7.40 (dd, J=7.7, 1.5Hz, 1H), 7.29-7.33 (m, 1H), 7.23-7.28 (m, 3H), 7.10-7.19 (m, 3H), 6.12(br. s., 1H), 4.62 (br. s., 1H), 3.62 (br. s., 1H), 3.52 (br. s., 1H),3.32 (br. s., 1H), 3.20 (s, 3H), 2.92 (s, 1H), 2.09 (br. s., 2H), 1.84(br. s., 2H). LC-MS: m/z 558.1 (M+H)⁺

General Procedure 48

Step A:

To a solution of the corresponding Aryl Bromide (1.0 eq.) in anhydrousTHF was added a solution of n-BuLi in THF (1.05 eq.) dropwise at −78° C.After the addition, the mixture was stirred at −78° C. for about 0.5hour. Then a solution of Cbz-4-piperidone in THF was added dropwise viaa syringe at −78° C. After the addition was complete, the resultingmixture was stirred at −78° C. under N₂ for 2 h, and then allowed towarm to r.t. The reaction mixture was quenched by addition of satd.NH₄Cl solution, and the resulting mixture was extracted with EtOAc (50mL, 30 mL). The combined organic phase was washed with brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified astandard method to afford compound 48B, which was confirmed by LCMS.

Step B:

To a round bottom flask was added the corresponding compound 48B (0.2mmol), Pd/C (20 mg), and methanol (5 mL). The mixture was stirred atroom temperature for 16 hrs under hydrogen atmosphere. The reactionmixture was filtered, and the resulting solution was concentrated togive the desired product 48C. The crude product was used directly forthe next step without further purification.

Step C:

To a round-bottomed flask was added compound 48C (0.1 mmol, 1 eq.), DMF(5 mL), DIPEA (0.3 mmol, 3.0 eq.), HBTU (0.12 mmol, 1.2 eq.), and 48E(0.1 mmol, 1 eq.) sequentially. The reaction mixture was stirred at roomtemperature overnight or until TLC indicated that s.m. was consumed. Themixture was diluted with brine, extracted with ethyl acetate, theorganic layer was dried with anhydrous Na₂SO₄, filtered, and filtratewas concentrated. The desired product 48D was purified by a method.

Compound 410:N-[4-[4-hydroxy-4-(1H-pyrazol-4-yl)piperidine-1-carbonyl]phenyl]benzothiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 12.57 (s, 1H), 10.76 (s, 1H), 9.66 (s, 1H),8.50 (dd, J=8.1, 1.0 Hz, 1H), 8.11 (dd, J=7.6, 1.0 Hz, 1H), 7.65 (t,J=7.9 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 7.20 (d, J=8.6 Hz, 2H), 7.12(t, J=9.8 Hz, 2H), 4.90 (s, 1H), 4.07 (s, 1H), 3.21 (s, 3H), 1.73 (s,4H). LC-MS: m/z 484.7 (M+H)⁺

Compound 411:N-[4-[4-hydroxy-4-(1-methylpyrazol-4-yl)piperidine-1-carbonyl]phenyl]benzothiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.23-8.16 (m, 1H), 8.10 (dd,J=7.5, 0.9 Hz, 1H), 7.93 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.41 (d, J=2.0Hz, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 6.10 (d, J=2.0Hz, 1H), 4.50 (s, 1H), 4.10 (s, 3H), 3.59 (s, 1H), 3.40 (m, 2H), 1.99(s, 2H), 1.87 (s, 2H). LC-MS: m/z 498.7 (M+H)⁺

Compounds 412

¹H NMR (METHANOL-d₄) δ: 9.47 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.11 (d,J=7.5 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.29-7.37 (m, 1H), 7.12-7.26 (m,4H), 6.10-6.21 (m, 1H), 4.27-4.48 (m, 1H), 4.03 (s, 3H), 3.39-3.60 (m,2H), 1.81-2.11 (m, 5H). LC-MS: m/z 498.7 (M+H)⁺

The following compounds depicted in Table 4 below were prepared usingthe same general procedure as described above.

TABLE 4 Compound LC-MS: m/z No (M + H)⁺ 267 440.2 268 520.2 270 606.1271 604.1 272 504.2 273 546.2 274 456.2 275 470.2 276 518.2 277 560.1278 513.2 281 485.1 283 502.2 284 546.2 285 519.2 286 507.1 287 519.2288 495.2 290 524.1 292 498.2 293 542.1 294 495.1 296 426.1 297 519.2298 489.2 299 485.1 300 488.2 301 469.2 302 524.1 304 519.2 306 489.2307 535.1 308 551.1 310 493.2 311 506.1 313 523.1 315 452.2 316 511.1317 476.2 318 511.1 319 488.2 320 516.2 321 519.2 323 490.2 325 535.1326 522.2 327 495.2 330 558.2 331 476.2 269 474.6 280 529.0 289 485.6303 547.0 309 492.6 312 457.6 314 475.6 322 487.0 324 432.6 384 472.6413 496.6 414 514.7 415 459.6 416 485.6 417 530.0 418 562.0 419 475.6443 531.7 444 546.6

General Procedure 50

Step A:

To a solution of 4-iodo-3-methylisothiazole (50A, 225 mg, 1.0 mmol) inTHF (10 mL) was added ethylmagnesium bromide (2N, 0.55 mL, 1.1 mmol) at0° C. under N₂ atmosphere. The reaction mixture was stirred at 0° C. for3 hrs, and then a solution of tert-butyl4-formylpiperidine-1-carboxylate (213 mg, 1.0 mmol) in THF (1 mL) wasadded dropwise to the above solution at −10° C. under N₂ atmosphere. Thereaction mixture was stirred at r.t. under N₂ overnight. The reactionmixture was quenched by sat. NH₄Cl solution, and the resulting mixturewas extracted with EtOAc twice. The combined organic phase was washedwith brine, dried over anhydrous Na₂SO₄, filtered, and the filtrateconcentrated in vacuo to afford 50B. LC-MS: m/z 313.5 (M+H)⁺.

¹H NMR (CHLOROFORM-d) δ: 8.52 (s, 1H), 4.62 (d, J=7.1 Hz, 1H), 4.18 (dd,J=24.2, 9.9 Hz, 2H), 3.52 (s, 1H), 2.68 (m, 2H), 2.51 (s, 3H), 1.93 (d,J=13.0 Hz, 1H), 1.72-1.62 (m, 2H), 1.47 (s, 9H), 1.39-1.11 (m, 2H).

Step B:

To a solution of tert-butyl4-(hydroxy(3-methylisothiazol-4-yl)methyl)piperidine-1-carboxylate (50B,60 mg, 0.192 mmol) in DCM (5 mL) was added DIPEA (28 mg, 0.212 mmol),followed by MsCl (24.3 mg, 0.212 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 0.5 h. Then the reaction mixture was allowed towarm to r.t. and stirred for an additional 1 h. The mixture wasextracted with DCM (10 mL, twice). The combined organic phase was washedwith brine, dried over anhy. Na₂SO₄, filtered, and the filtrate wasconcentrated in vacuo to afford 50C. LC-MS: m/z 331.1 (M+H)⁺.

¹H NMR (CHLOROFORM-d) δ: 8.57 (s, 1H), 4.77 (d, J=8.4 Hz, 1H), 4.17 (d,J=37.5 Hz, 2H), 2.82-2.59 (m, 2H), 2.54 (s, 3H), 2.19-1.99 (m, 2H), 1.47(s, 9H), 1.36-1.14 (m, 3H).

Step C:

To a solution of tert-butyl4-(chloro(3-methylisothiazol-4-yl)methyl)piperidine-1-carboxylate (50C,78 mg, 0.236 mmol) in DCM (0.5 mL) was added DBU (3 mL) at r.t. Thereaction mixture was stirred at 120° C. in microwave for 0.5 h. Then thereaction mixture was cooled to r.t. The resulting mixture was extractedwith EtOAc (10 mL, twice). The combined organic phase was washed withbrine, dried over anhy. Na₂SO₄, filtered, and the filtrate concentratedin vacuo to afford 50D. LC-MS: m/z 295.1 (M+H)⁺. ¹H NMR (CHLOROFORM-d)δ: 8.27 (s, 1H), 6.13 (s, 1H), 3.59-3.49 (m, 2H), 3.47-3.38 (m, 2H),2.46 (s, 3H), 2.38 (m, 4H), 1.50 (s, 9H).

Step D:

To a solution of tert-butyl4-((3-methylisothiazol-4-yl)methylene)piperidine-1-carboxylate (50D, 147mg, 0.5 mmol) in acetone (12 mL) and H₂O (2 mL) was added dropwise H₂SO₄(123 mg, 1.25 mmol) in H₂O (0.6 mL), followed with NBS (134 mg, 0.75mmol) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 3 hrs.Then the reaction mixture was extracted with EtOAc (10 mL, twice). Thecombined organic phase was washed with brine, dried over anhy. Na₂SO₄,filtered, and the filtrate was concentrated in vacuo to afford 50E.LC-MS: m/z 391.1 (M+H)⁺.

Step E:

To a solution of tert-butyl4-bromo-4-(hydroxy(3-methylisothiazol-4-yl)methyl)piperidine-1-carboxylate(50E, 39.1 mg, 0.1 mmol) in THF (2 mL) was added NaH (4.0 mg, 0.1 mmol)at 0° C. The reaction mixture was stirred at r.t. for 2 hrs. Then thereaction mixture was quenched by Sat. NH₄Cl. The mixture was extractedwith EtOAc (10 mL, twice). The combined organic phase was washed withbrine, dried over anhy. Na₂SO₄, filtered, and the filtrate wasconcentrated in vacuo to afford 50F. LC-MS: m/z 211.2 (M+H-100)⁺.

Step F:

To a solution of tert-butyl2-(3-methylisothiazol-4-yl)-1-oxa-6-azaspiro[2.5]octane-6-carboxylate(10 mg, 0.032 mmol) and Tetrabutyl ammonium bromide (21 mg, 0.065 mmol)in DCM (3 mL) was added dropwise borontrifluro ether complex (15 mg,0.048 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10min. Then the reaction mixture was extracted with DCM (10 mL, twice).The combined organic phase was washed with brine, dried over anhy.Na₂SO₄, filtered, and the filtrate was concentrated in vacuo to afford50G. LC-MS: m/z 211.2 (M+H-56)⁺.

¹H NMR (CHLOROFORM-d) δ: 9.03 (s, 1H), 5.02 (s, 1H), 4.12-3.83 (m, 2H),3.20-2.93 (m, 2H), 2.52 (s, 3H), 2.18-2.03 (m, 2H), 1.55 (dd, J=13.5,2.7 Hz, 2H), 1.47 (s, 9H).

Step G:

To a solution of tert-butyl4-(bromo(3-methylisothiazol-4-yl)methyl)-4-hydroxypiperidine-1-carboxylate(50G, 58 mg, 0.15 mmol) and AIBN (4.9 mg, 0.03 mmol) in toluene (5 mL)was added Tributyltin hydride (65.1 mg, 0.223 mmol) at r.t. under N₂.The reaction mixture was stirred at 90° C. for 8 h, when TLC showed thatthe reaction was complete. The reaction mixture was concentrated invacuo to afford 5011. LC-MS: m/z 313.2 (M+H)⁺.

Step H:

To a solution of tert-butyl4-hydroxy-4-((3-methylisothiazol-4-yl)methyl)piperidine-1-carboxylate(50H, 55 mg) in DCM (5 mL), was added TFA (1 mL), the reaction mixturewas stirred at room temperature for about 2 hours, when LCMS detected nos.m. The reaction mixture was concentrated to afford the desired product50I. The crude product was used for the next step directly withoutfurther purification. LC-MS: m/z 213.2 (M+H)⁺.

Step I:

To a solution of 4-(arylsulfonamido)benzoic acid (0.18 mmol) in DCM (5mL) was added HBTU (80 mg, 0.22 mmol), DIPEA (70 mg, 0.54 mmol) and4-((3-methylisothiazol-4-yl)methyl)piperidin-4-ol (50I, 38 mg, 0.18mmol), sequentially at room temperature. The reaction mixture wasstirred at room temperature for 1 hour. The mixture was poured intowater and extracted with EtOAc (20 mL) twice. The combined organic layerwas washed with brine and dried over anhy. Na₂SO₄. The combined organiclayer was concentrated in vacuo and purified using standard techniquesto afford the desired product.

The following compounds were prepared according to General Procedure 50.

Compound 497:N-(4-(4-hydroxy-4-((3-methylisothiazol-4-yl)methyl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.08 (s, 2H), 8.45 (dd, J=7.3, 1.4 Hz, 1H),8.40-8.32 (m, 2H), 8.05 (s, 1H), 7.86 (dd, J=8.4, 7.4 Hz, 1H), 7.19 (d,J=8.5 Hz, 2H), 7.09 (d, J=8.6 Hz, 2H), 4.43 (s, 1H), 3.47 (s, 1H), 3.32(s, 1H), 3.10 (s, 1H), 2.79 (s, 2H), 2.47 (s, 3H), 1.60-1.35 (m, 4H).LC-MS: m/z 524.4 (M+H)⁺.

Compound 519:N-(4-(4-hydroxy-4-((3-methylisothiazol-4-yl)methyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-7-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.49 (s, 1H), 8.56 (s, 1H), 8.33 (dd, J=8.1,0.9 Hz, 1H), 8.12 (dd, J=7.6, 1.0 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.20(s, 4H), 4.32 (d, J=6.8 Hz, 1H), 3.39 (s, 1H), 3.19 (m, 2H), 2.81 (s,2H), 2.46 (s, 3H), 1.66-1.40 (m, 4H). LC-MS: m/z 529.77 (M+H)⁺

General Procedure 51

Step A:

To a suspension of benzo[d][1,3]dioxol-4-amine (800 mg, 5.84 mmol) inHCl (30 mL) was added dropwise NaNO₂ (604.4 mg, 8.76 mmol) in water (2mL) at 0° C. After the addition, the reaction mixture was stirred at 0°C. for 2 h. To a solution of CuCl (867.2 mg, 8.76 mmol) in CH₃COOH (30mL) was pumped SO₂ for 3 h at 20° C., and the resulting reaction mixturewas added to the previous solution at r.t. Then the reaction mixture wasstirred at 40° C. overnight. The reaction mixture was quenched by sat.NH₄Cl solution, and the resulting mixture was extracted with EtOAc (50mL, twice). The combined organic phase was washed with brine, dried overanhy. Na₂SO₄ and concentrated in vacuo to give 51B. LC-MS: m/z 221.6(M+H)⁺.

Step B: Compound 448:N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)benzo[d][1,3]dioxole-4-sulfonamide

To a suspension of the corresponding 51C (124 mg, 0.45 mmol) andsulfonyl chloride (100 mg, 0.45 mmol) in 30 mL of anhydrous THF, wasadded pyridine (1.0 mmol) at room temperature. The resulting mixture washeated and stirred at reflux for 6 h. The reaction mixture was cooled toroom temperature, and then extracted with EtOAc (100 mL×2). The combinedorganic phase was washed with brine, dried over anhy. Na₂SO₄,concentrated in vacuo and purified by standard methods. ¹H NMR(CHLOROFORM-d) δ: 7.32 (d, J=7.5 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 7.15(d, J=7.4 Hz, 2H), 6.99 (d, J=7.6 Hz, 1H), 6.90 (dd, J=10.3, 5.6 Hz,2H), 6.12 (s, 2H), 4.40 (s, 1H), 3.58-3.15 (m, 3H), 1.86 (dt, J=12.8,6.3 Hz, 1H), 1.58 (dd, J=29.1, 11.7 Hz, 4H), 1.44 (d, J=5.9 Hz, 2H),1.00 (d, J=6.6 Hz, 6H). LC-MS: m/z 461.7 (M+H)⁺.

General Procedure 52

Step A:

To a solution of the corresponding 4-chloroaryl reagent (0.9 mmol) inTHF (10 mL) was added dropwise n-BuLi (0.392 mL, 0.98 mmol) at −78° C.under N₂. After 1 h stirring at −78° C., a solution of tert-butyl1-oxa-6-azaspiro[2.5]octane-6-carboxylate (200 mg, 0.98 mmol) in 1 mL ofTHF was added dropwise to the reaction mixture, followed by BF₃.OEt₂(299.3 mg, 0.98 mmol) at −78° C. under N₂. The reaction mixture wasstirred at −78° C. for 3 h, and then the reaction mixture was allowed towarm to r.t. and stirred at r.t. overnight. The reaction mixture wascooled to −30° C. and quenched by Sat. NH₄Cl. The resulting mixture wasextracted with EtOAc (50 mL, twice). The combined organic phase waswashed with brine, dried over anhy. Na₂SO₄ and concentrated in vacuo.The residue was purified by standard methods to afford 52B.

Step B:

To a solution of compound 52B (150 mg) in DCM (5 mL), was added TFA (1mL), the reaction mixture was stirred at room temperature for about 2hours, when LCMS detected no s.m. The reaction mixture was concentratedto afford the desired product 52C. The crude product was used for thenext step directly without further purification.

Step C:

To a solution of 4-(aryl-4-sulfonamido)benzoic acid (0.45 mmol) in DCM(5 mL) was added HBTU (180 mg, 0.54 mmol), DIPEA (174 mg, 1.35 mmol) andcompound 52C (0.45 mmol), sequentially at room temperature. The reactionmixture was stirred at room temperature overnight. The mixture waspoured into water and extracted with DCM (20 mL) twice. The combinedorganic layer was washed with brine and dried over anhy. Na₂SO₄,concentrated in vacuo, and purified by standard methods to afford thedesired compound.

The following compounds were prepared according to General Procedure 52.

Compound 489:N-(4-(4-((4-chlorothiazol-2-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.31 (s, 1H), 8.19 (dd, J=8.2, 1.0 Hz, 1H),8.09 (dd, J=7.5, 1.0 Hz, 1H), 7.92 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.19(d, J=8.5 Hz, 2H), 7.10 (d, J=8.6 Hz, 2H), 7.02 (s, 1H), 4.36 (s, 1H),3.37 (dd, J=50.3, 26.0 Hz, 3H), 3.10 (s, 2H), 1.57 (dd, J=28.7, 9.8 Hz,4H). LC-MS: m/z 549.2 (M+H)⁺.

Compound 462:N-(4-(4-hydroxy-4-((1-methyl-1H-pyrazol-4-yl)methyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 9.49 (s, 1H), 8.34 (dd, J=8.1, 1.0 Hz, 1H),8.13 (dd, J=7.6, 1.1 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.38 (d, J=1.9 Hz,1H), 7.19 (d, J=4.6 Hz, 4H), 6.15 (d, J=1.9 Hz, 1H), 4.29 (s, 1H), 3.85(d, J=4.4 Hz, 3H), 3.40 (s, 2H), 3.28 (s, 1H), 2.85 (s, 2H), 1.71-1.45(m, 4H). LC-MS: m/z 512.1 (M+H)⁺.

Compound 461:N-(4-(4-hydroxy-4-((1-methyl-1H-pyrazol-5-yl)methyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (METHANOL-d₄) δ: 9.48 (s, 1H), 8.30 (d, J=8.1 Hz, 1H), 8.10 (d,J=7.6 Hz, 1H), 7.55 (t, J=7.8 Hz, 1H), 7.37 (d, J=1.9 Hz, 1H), 7.19 (s,4H), 6.13 (d, J=1.9 Hz, 1H), 4.29 (s, 1H), 3.83 (s, 3H), 3.33 (s, 2H),3.28 (s, 1H), 2.84 (s, 2H), 1.49-1.65 (m, 4H). LC-MS: m/z 512.1 (M+H)⁺.

Compound 508:N-(4-(4-hydroxy-4-((1-methyl-1H-pyrazol-5-yl)methyl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (METHANOL-d₄) δ: 9.07 (s, 2H), 8.45 (dd, J=7.3, 1.3 Hz, 1H), 8.36(dd, J=8.6, 1.3 Hz, 1H), 8.06 (s, 1H), 7.85 (dd, J=8.5, 7.4 Hz, 1H),7.45 (d, J=1.6 Hz, 1H), 7.14-7.25 (m, J=8.6 Hz, 2H), 6.98-7.14 (m, J=8.6Hz, 2H), 6.10 (d, J=1.6 Hz, 1H), 4.41 (br. s., 1H), 3.87 (s, 3H), 3.43(br. s., 1H), 3.31 (br. s., 1H), 3.12 (br. s., 1H), 2.81 (s, 2H), 1.64(br. s., 2H), 1.51-1.60 (m, 2H). LC-MS: m/z 507.5 (M+H)⁺

General Procedure 53

Step A:

tert-butyl 4-oxopiperidine-1-carboxylate (1 g, 5.02 mmol) was dissolvedin 2-(bromomethyl)-3,3,3-trifluoroprop-1-ene (1900 mg, 10.038 mol) inTHF (20 mL) and saturated ammonium chloride solution (5 mL). Thereaction was cooled to 10° C. and zinc dust (656 mg, 10 mmol) was addedportionwise. After addition the reaction mixture was stirred overnight.TLC was taken (heptane/EtOAc 7:1) and showed full conversion of s.m. toproduct. The reaction mixture was diluted with water (5 mL), and wasextracted with MTBE. The organic layers were combined and washed with asaturated solution of NaHCO₃, brine, dried and evaporated to give thecrude product which was used in the next step without furtherpurification.

Step B:

To a vial was added with tert-butyl4-hydroxy-4-(2-(trifluoromethyl)allyl)piperidine-1-carboxylate (400 mg,1.29 mmol), EtOH (10 mL), 10% Pd/C (250 mg), and AcOH (0.5 mL). Themixture was stirred at 40° C. for 16 hrs under H₂ atmosphere. Then thereaction mixture was filtered, and evaporated to give the crude productwhich was used in the next step without further purification.

Step C:

To a vial was added with compound 53C (100 mg, 0.323 mmol), DCM (5 mL)and HCl/MeOH (4.5 M, 1 mL), the mixture was stirred at 0-15° C. for 16hrs. The mixture was concentrated in vacuo to obtain the crude product,which was used directly for the next step.

Step D:

To a solution of the corresponding 4-(aryl-4-sulfonamido)benzoic acid(0.45 mmol) in DCM (5 mL) was added HBTU (180 mg, 0.54 mmol), DIPEA (174mg, 1.35 mmol) and compound 53D (0.45 mmol), sequentially at roomtemperature. The reaction mixture was stirred at room temperatureovernight. The mixture was poured into water and extracted with DCM (20mL) twice. The combined organic layer was washed with brine and driedover anhy. Na₂SO₄, concentrated in vacuo, and purified by standardmethods to afford the desired product.

The following compounds were prepared according to General Procedure 53.

Compound 456:2-amino-N-(4-(4-hydroxy-4-(3,3,3-trifluoro-2-methylpropyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 7.79 (dd, J=7.9, 1.2 Hz, 1H), 7.73 (dd, J=7.8,1.1 Hz, 1H), 7.19-7.31 (m, 4H), 7.07 (t, J=7.8 Hz, 1H), 4.23-4.34 (m,1H), 3.40 (br. s., 2H), 3.21 (br. s., 1H), 2.51 (d, J=7.3 Hz, 1H), 1.84(d, J=14.8 Hz, 1H), 1.67 (d, J=17.5 Hz, 1H), 1.48-1.59 (m, 2H), 1.43(dd, J=14.6, 7.9 Hz, 1H), 1.33 (d, J=18.0 Hz, 1H), 1.22 (d, J=7.0 Hz,3H). LC-MS: m/z 543.5 (M+H)⁺

Compound 458:4-hydroxy-N-(4-(4-hydroxy-4-(3,3,3-trifluoro-2-methylpropyl)piperidine-1-carbonyl)phenyl)quinazoline-8-sulfonamide

¹H NMR (METHANOL-d₄) δ: 8.36-8.44 (m, 2H), 8.28 (s, 1H), 7.58 (tt,J=7.9, 1.0 Hz, 1H), 7.24 (s, 4H), 4.27 (br. s., 1H), 3.35-3.50 (m, 2H),3.20 (br. s., 1H), 2.50 (d, J=7.5 Hz, 1H), 1.84 (d, J=14.5 Hz, 1H), 1.67(d, J=15.6 Hz, 1H), 1.51 (br. s., 2H), 1.43 (dd, J=14.6, 7.9 Hz, 1H),1.24-1.37 (m, 1H), 1.21 (d, J=6.7 Hz, 3H). LC-MS: m/z 539.6 (M+H)⁺

General Procedure 54

Step A:

To a stirring solution of the tert-butyl4-methylenepiperidine-1-carboxylate (9.0 g, 45.4 mmol) in chloroform(150 mL) at 0° C. was added 3-Chloroperoxybenzoic acid (12.2 g, 70.4mmol) and the reaction mixture was stirred for 30 minutes at 0° C. andwas then allowed to warm up to room temperature. The reaction progresswas monitored by TLC, and additional portions of m-CPBA were added asneeded. Upon completion, the reaction mixture was diluted withchloroform (100 mL) and washed with 10% aq. Na₂SO₃ (2×60 mL), 10% aq.NaHCO₃ (2×150 mL) and brine (150 mL). The organic layer was dried overNa₂SO₄, filtered and concentrated and purified by standard methods togive 54B. ¹H NMR (400 MHz, CHLOROFORM-d) δ: 1.41-1.52 (m, 11H) 1.81(ddd, J=13.50, 9.34, 4.30 Hz, 2H) 2.70 (s, 2H) 3.44 (ddd, J=13.23, 9.60,3.76 Hz, 2H) 3.67-3.80 (m, 2H).

Step B:

To a stirred solution of malononitrile (1.45 g, 22.0 mmol) in THF (20mL) was added portionwise NaH (60% in oil, 845 mg, 21 mmol) at 0° C.under an inert atmosphere. After being stirred for 30 min at 0° C., asolution of compound 2 (900 mg, 4.22 mmol) in THF (10 mL) was added tothe reaction mixture at 0° C., and stirring was continued for 16 h atRT. The progress of the reaction was monitored by TLC. The reaction wasquenched with ice-cold water (100 mL) and extracted with EA (2×50 mL).The combined organic layers were washed with water (40 mL) and brine (40mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressureto obtain the crude material. Purification by silica gel columnchromatography (eluting with 45% EA/PE) afforded compound 54C. LC-MS:m/z 280.3 (M+H)⁺. NMR (400 MHz, CHLOROFORM-d) δ: 1.48 (s, 13H), 2.68 (s,2H), 3.17-3.37 (m, 3H), 3.71 (d, J=12.36 Hz, 2H), 3.93 (br. s., 1H).

Step C:

To a stirred solution of compound 54C (630 mg, 2.26 mmol) in EtOH (20mL) was added 50% hydrazine hydrate (0.7 mL), and the reaction mixturewas heated to reflux temperature for 4 hrs. The progress of the reactionwas monitored by TLC. The volatiles were evaporated under reducedpressure to afford compound 54D. LC-MS: m/z 312.3 (M+H)⁺. ¹H NMR (400MHz, CHLOROFORM-d) δ 1.35-1.58 (m, 13H), 2.25 (br. s., 2H), 3.05 (br.s., 2H), 3.76 (d, J=11.55 Hz, 2H), 4.79 (br. s., 6H).

Step D:

To a solution of 54D (100 mg, 0.32 mmol) in 50% aqueous hypophosphorousacid (10 ml) was added water (5.0 mL) at 0° C. while stirring. Asolution of NaNO₂ (500 mg, 7.2 mmol) in water (2.0 mL) was addeddropwise. The reaction mixture was then stirred continuously for 30 minat 0° C. and finally allowed to warm up to RT, and then stirred for 3.0h when LC-MS show full conversion of s.m. to product. Afterneutralization with saturated NaOH aqueous, the reaction mixture wasextracted with EA (2×50 mL). The combined organic layers were washedwith water (40 mL) and brine (40 mL), and then dried over anhydrousNa₂SO₄, filtered, and the filtrate was concentrated under reducedpressure to obtain the crude product 54E. LC-MS: m/z 182.2 (M+H)⁺.

Step E:

To a solution of the corresponding 4-(aryl-4-sulfonamido)benzoic acid(0.45 mmol) in DCM (5 mL) was added HBTU (180 mg, 0.54 mmol), DIPEA (174mg, 1.35 mmol) and compound 5 (0.45 mmol), sequentially at roomtemperature. The reaction mixture was stirred at room temperatureovernight. The mixture was poured into water and extracted with DCM (20mL) twice. The combined organic layer was washed with brine and driedover anhy. Na₂SO₄, concentrated in vacuo, and purified by standardmethods to afford the desired compound.

The following compounds were prepared according to General Procedure 54.

Compound 499:N-(4-(4-((1H-pyrazol-4-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ: 1.47 (d, J=6.18 Hz, 2H), 1.62 (br. s., 2H),2.67 (s, 2H), 3.09 (br. s., 3H), 4.39 (br. s., 1H), 7.08 (m, J=8.60 Hz,2H), 7.19 (m, J=8.60 Hz, 2H), 7.48 (s, 2H), 7.85 (dd, J=8.46, 7.39 Hz,1H), 8.04 (s, 1H), 8.36 (dd, J=8.33, 1.34 Hz, 1H), 8.45 (dd, J=7.25,1.34 Hz, 1H), 9.08 (s, 2H). LC-MS: m/z 493.4 (M+H)⁺

Compound 498:N-(4-(4-((1H-pyrazol-4-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ 1.32 (br. s., 4H), 2.60 (s, 2H), 3.03 (br. s.,1H), 3.20 (br. s., 2H), 4.05 (br. s., 1H), 7.11 (q, J=8.87 Hz, 4H), 7.36(br. s., 2H), 7.65 (t, J=7.92 Hz, 1H), 8.11 (dd, J=7.52, 1.07 Hz, 1H),8.50 (dd, J=8.06, 1.07 Hz, 1H), 9.65 (s, 1H), 10.75 (s, 1H), 12.50 (br.s., 1H). LC-MS: m/z 498.1 (M+H)⁺

General Procedure 55

Step A:

To a solution of Ceric ammonium nitrate (CAN) (1.1 g, 1.88 mmol) inacetonitrile (20 mL) were addedtert-butyl-4-methylenepiperidine-1-carboxylate (197 mg, 1.0 mmol) andpentane-2,4-dione (200 mg, 2.0 mmol) in acetonitrile (10 mL) at r.t.,and the reaction mixture was stirred for 2 hrs at RT. The mixture waspoured into water (50 mL) and extracted with EtOAC (3×60 mL), theorganic layer was then washed with water (60 mL) and brine (60 mL),dried over anhy. Na₂SO₄, and concentrated in vacuo. The residue waspurified by standard methods (PE/EA=4/1) to give 55B. ¹H NMR(CHLOROFORM-d) δ 1.42-1.44 (m, 9H), 1.52-1.65 (m, 3H), 1.76 (br. s.,1H), 2.16 (s, 3H), 2.18 (s, 3H), 2.65-2.71 (m, 2H), 3.35 (ddd, J=13.30,9.81, 3.22 Hz, 2H), 3.59 (d, J=13.16 Hz, 2H). LC-MS: m/z 296.4 (M+H)⁺

Step B:

To a stirred solution of compound tert-butyl3-acetyl-2-methyl-1-oxa-8-azaspiro[4.5]dec-2-ene-8-carboxylate (570 mg,1.93 mmol) in EtOH (20 mL) was added 50% hydrazine hydrate (1.0 mL), andthe reaction mixture stirred at r.t. overnight. The reaction mixture wasevaporated under reduced pressure to afford 55C. LC-MS: m/z 310.4 (M+H)⁺

A similar procedure to preparation of 55D was employed. LC-MS: m/z 311.4(M+H)⁺

Step C:

55C or 55D (200 mg, 0.65 mmol) was added to solution of hydrogenchloride in dioxane (4M, 3.0 mL) and the resulting solution was stirredovernight at room temperature. The solvent was evaporated in vacuo andthe residue was treated with diethyl ether. The resultant suspension wasfiltered to give the desired compound. LC-MS: m/z 210.4 (M+H)⁺

Step D:

A similar procedure to General Procedure 54, step E was used.

The following compounds were prepared according to General Procedure 55.Compound 512:N-(4-(4-((3,5-dimethyl-1H-pyrazol-4-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ 1.44-1.51 (m, 2H), 1.57 (dd, J=12.36, 6.98 Hz,2H), 2.24 (s, 6H), 2.51 (s, 2H), 3.32 (br. s., 3H), 4.44 (br. s., 1H),7.09 (m, J=8.60 Hz, 2H), 7.20 (m, J=8.60 Hz, 2H), 7.86 (dd, J=8.46, 7.39Hz, 1H), 8.08 (br. s., 1H), 8.36 (dd, J=8.60, 1.34 Hz, 1H) 8.46 (dd,J=7.39, 1.21 Hz, 1H), 9.08 (s, 2H), 11.22 (br. s., 1H). LC-MS: m/z 521.5(M+H)⁺

Compound 514:N-(4-(4-(3,5-dimethyl-1H-pyrazol-4-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (400 MHz, METHANOL-d₄) δ: 1.51-1.60 (m, 4H), 2.25 (s, 6H), 2.54(s, 2H), 3.09-3.40 (m, 3H), 4.35 (br. s., 1H), 7.13-7.30 (m, 4H), 7.58(t, J=7.92 Hz, 1H), 8.12 (dd, J=7.52, 1.07 Hz, 1H), 8.34 (dd, J=8.19,0.94 Hz, 1H), 9.49 (s, 1H). LC-MS: m/z 526.5 (M+H)⁺

Compound 521:N-(4-(4-((3,5-dimethylisoxazol-4-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (400 MHz, METHANOL-d₄) δ: 1.33-1.47 (m, 2H), 1.57 (br. s., 2H),2.18 (s, 3H), 2.30 (s, 3H), 2.39-2.46 (m, 2H), 3.05 (br. s., 1H), 3.26(br. s., 1H), 3.35 (d, J=4.30 Hz, 1H), 4.32 (d, J=12.89 Hz, 1H), 7.17(s, 4H), 7.84-7.93 (m, 1H), 8.28 (dd, J=8.60, 1.07 Hz, 1H), 8.48 (dd,J=7.39, 1.21 Hz, 1H), 9.00 (d, J=1.88 Hz, 1H), 9.09 (d, J=1.61 Hz, 1H).LC-MS: m/z 522.8 (M+H)⁺

Compound 520:N-(4-(4-((3,5-dimethylisoxazol-4-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (400 MHz, METHANOL-d₄) δ: 1.43 (d, J=16.12 Hz, 1H), 1.51 (br. s.,1H), 1.61 (br. s., 2H), 2.17-2.24 (m, 3H), 2.29-2.39 (m, 3H), 2.47 (s,2H), 3.10 (br. s., 2H), 3.41 (br. s., 1H), 4.32 (d, J=6.98 Hz, 1H), 7.19(s, 4H), 7.59 (t, J=7.79 Hz, 1H), 8.06-8.20 (m, 1H), 8.34 (d, J=8.06 Hz,1H), 8.51 (br. s., 1H), 9.50 (br. s., 1H). LC-MS: m/z 527.6 (M+H)⁺

General Procedure 56

Step A:

A magnetically stirred solution of 1,4-cyclohexanedione monoethyleneacetal 56A (5.00 g, 32.0 mmol) in MeOH (30 mL) at 0° C., was treatedwith sodium borohydride (1.57 g, 41.5 mmol). After 0.5 h, the reactionmixture was warmed to 18° C. and stirred at this temperature for anadditional 0.5 h. The solvent was then removed under reduced pressureand the resulting residue was partitioned between H₂O (30 mL) and CH₂Cl₂(30 mL). The separated aqueous phase was extracted with CH₂Cl₂ (20 mL)and the combined organic fractions were then dried over MgSO4, filteredand the filtrate was concentrated under reduced pressure to afford 56B.LC-MS: m/z 159.1 (M+H)⁺

Step B:

A magnetically stirred solution of alcohol 56B (3.00 g, 19.0 mmol) indry CH₂Cl₂ (20 mL) was treated with carbon tetrabromide (7.55 g, 22.8mmol) and the resulting mixture was cooled to 0° C. Triphenylphosphine(5.97 g, 22.8 mmol) was then added and stirring was continued at 0° C.under a nitrogen atmosphere for 5 hrs. After this time H₂O (50 mL),followed by CH₂Cl₂ (80 mL) were added to the reaction mixture, theorganic phase was separated and the aqueous phase was extracted withCH₂Cl₂ (80 mL). The combined organic fractions were then dried (MgSO₄),filtered, and the filtrate was concentrated under reduced pressure, andpurified by standard methods to afford 56C. LC-MS: m/z 221.1 (M+H)⁺

Step C:

To a solution of Li (70 mg, 1.1 mmol) in THF (10 mL) was added dropwise1-benzoylpiperidin-4-one (103 mg, 0.55 mmol) at −78° C. under N₂. After1 h, 8-bromo-1,4-dioxaspiro[4.5]decane (120 mg, 0.55 mmol) in THF (1 mL)was added dropwise to the reaction mixture at −78° C. under N₂. Thereaction mixture was stirred at −78° C. for 3 h, and then the reactionmixture was allowed to warm up to r.t. and stirred at r.t. overnight.The reaction mixture was cooled to −30° C. and quenched by Sat. NH₄Cl.The resulting mixture was extracted with EtOAc (50 mL, twice). Thecombined organic phase was washed with brine, dried over anhy. Na₂SO₄and concentrated in vacuo. The residue was purified by standard methodsto afford 56D. LC-MS: m/z 332.2 (M+H)⁺

Step D:

56D (300 g, 1.1 mmol) was dissolved in water (5 mL), conc. hydrochloricacid (5 mL) was added and the mixture was stirred at r.t. for 2 hrs. Thereaction mixture was extracted with diethyl ether (10 mL, twice), theaqueous phase was neutralized with 2 N NaOH while cooling with ice. Themixture was extracted with DCM (10 mL, twice) and the extract wascombined, dried and concentrated to afford 56E (213 mg). LC-MS: m/z288.2 (M+H)⁺

Step E:

To a solution of compound 56E (213 mg, 0.74 mmol) in ethanol (10 mL) wasadded sodium borohydride (80 mg, 2.1 mmol), and the mixture was stirredat r.t. for 3 h. The reaction mixture was concentrated in vacuo, waterwas added to the residue, and extraction with ethyl acetate (10 mL,twice) was carried out. The combined extracts were washed with water andsaturated sodium chloride solution, dried (Na₂SO₄) and concentrated invacuo to afford 56F. LC-MS: m/z 290.2 (M+H)⁺

Step F:

A suspension of compound 5611 (182 mg, 0.63 mmol) and Pd/C (10%, 20 mg)in MeOH (20 mL) was hydrogenated at 3 bar hydrogen pressure at r.t. for2 hours. The reaction mixture was filtered off and the filtrate wasevaporated in vacuo to afford 56G. LC-MS: m/z 200.2 (M+H)⁺

Step G:

To a solution of the corresponding 4-(aryl-4-sulfonamido)benzoic acid (1eq.) in DCM (5 mL) was added HBTU (1.2 eq.), DIPEA (3 eq.) and compound7 (1.0 eq.), sequentially at room temperature. The reaction mixture wasstirred at room temperature overnight. The mixture was poured into waterand extracted with DCM (20 mL) twice. The combined organic layer waswashed with brine, dried over anhy. Na₂SO₄, concentrated in vacuo, andpurified by standard methods to afford the desired compound.

The following compounds were prepared according to General Procedure 56.

Compound 502:N-(4-(4-hydroxy-4-(4-hydroxycyclohexyl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ 1.68 (br. s., 28H), 1.84 (s, 4H), 1.81 (s, 5H),2.07 (s, 4H), 2.05 (s, 4H), 3.09 (br. s., 4H), 3.30 (d, J=18.27 Hz, 4H),3.41-3.60 (m, 8H), 4.46 (br. s., 3H), 7.08 (d, J=8.60 Hz, 7H), 7.19 (d,J=8.33 Hz, 7H), 7.85 (dd, J 8.46, 7.39 Hz, 4H), 8.04 (s, 4H), 8.35 (dd,J=8.33, 1.34 Hz, 3H), 8.45 (dd, J=7.52, 1.34 Hz, 3H), 9.07 (s, 7H).LC-MS: m/z 511.7 (M+H)⁺

Compound 501:N-(4-(4-hydroxy-4-(4-hydroxycyclohexyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ 1.68 (br. s., 28H), 1.84 (s, 4H), 1.81 (s, 5H),2.07 (s, 4H), 2.05 (s, 4H), 3.09 (br. s., 4H), 3.30 (d, J=18.27 Hz, 4H),3.41-3.60 (m, 8H), 4.46 (br. s., 3H), 7.08 (d, J=8.60 Hz, 7H), 7.19 (d,J=8.33 Hz, 7H), 7.85 (dd, J=8.46, 7.39 Hz, 4H), 8.04 (s, 4H), 8.35 (dd,J=8.33, 1.34 Hz, 3H), 8.45 (dd, J=7.52, 1.34 Hz, 3H), 9.07 (s, 7H).LC-MS: m/z 516.7 (M+H)⁺

General Procedure 57

Step A: To a stirred suspension of ethyl4-(2,3-diaminophenylsulfonamido)benzoate (5 g, 15 mmol) in ethanol (50mL) was added a solution of ethyl glyoxalate in toluene (1.6 M, 3 mL, 18mmol) over a period of 5 min. After heating to 45° C. for 10 h, themixture was left at r.t. under stirring. The precipitate was filteredand the cake was washed with water and dried to give 57B. LC-MS: m/z 374(M+H)⁺. The filtrate was concentrated and purified by standard methodsto provide 57C. LC-MS: m/z 374 (M+H)⁺

Step B: A solution of ethyl4-(3-oxo-3,4-dihydroquinoxaline-5-sulfonamido)benzoate (500 mg, 1.34mol) in 10 mL of POCl₃ (10 mL) was heated at reflux for 3 h, theresulting mixture was added carefully into water (40 mL), the aqueouslayer was extracted with EtOAc (50 mL, twice), the combined organiclayers were washed with brine, dried over Na₂SO₄ and evaporated toprovide. The crude product was purified by standard methods to provide57D. LC-MS: m/z 392(M+H)⁺

Step C: a similar procedure as Step B was used.

Step D: To a solution of ethyl4-(3-chloroquinoxaline-5-sulfonamido)benzoate (360 mg, 0.92 mmol) andCuI (174 mg, 0.92 mmol) in 10 mL DMSO was added ammonia water dropwise.After the addition was complete, the reaction mixture was stirred at110° C. overnight. Then the reaction mixture was cooled to roomtemperature, and poured into water (50 mL), the aqueous layer wasextracted with EtOAc (5×50 mL), the combined organic layers were washedwith brine, dried over Na₂SO₄, and concentrated to provide crude 57E,and the crude product was used in the next step without furtherpurification. ¹H NMR (CHLOROFORM-d) δ: 8.33 (br. s., 1H), 7.77-7.84 (m,1H), 7.70-7.77 (m, 1H), 7.22 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H),7.07-7.11 (m, 1H), 6.25 (br. s., 1H), 4.35 (br. s., 1H), 3.44 (br. s.,1H), 3.36 (br. s., 1H), 3.22 (br. s., 1H), 3.13 (s, 3H), 1.83 (dd,J=12.9, 6.4 Hz, 2H), 1.65 (br. s., 2H), 1.49 (br. s., 1H), 1.41 (d,J=5.9 Hz, 2H), 0.98 (d, J=6.7 Hz, 6H). LC-MS: m/z 373(M+H)⁺

Step E: a similar procedure as Step D was used.

Step F: To a solution of the corresponding compound 57E (300 mg, 0.8mmol) in EtOH/H₂O (10 mL/3 mL) was added LiOH.H₂O (160 mg, 4.0 mmol) andthe resulting suspension was stirred at 70° C. overnight. The solventwas concentrated and the residue was partitioned between aqueous 2 N HCland EtOAc. The organic layer was separated and washed with water andbrine, dried over Na₂SO₄ and concentrated to give the desired crudeproduct 57F, which was used in subsequent reaction without furtherpurification. LC-MS: m/z 345.1 (M+H)⁺

Step G: a similar procedure as Step F was used.

Step H: To a solution of the corresponding 4-(aryl-4-sulfonamido)benzoicacid (1 eq.) in DCM (5 mL) was added HBTU (1.2 eq.), DIPEA (3 eq.) andcompound 57F (1.0 eq.), sequentially at room temperature. The reactionmixture was stirred at room temperature overnight. The mixture waspoured into water and extracted with DCM (20 mL) twice. The combinedorganic layer was washed with brine and dried over anhy. Na₂SO₄,concentrated in vacuo, and purified by standard methods to provide 465.

Step I: a similar procedure as Step H was used.

The following compounds were prepared according to General Procedure 57.

Compound 465:3-amino-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (400 MHz, METHANOL-d₄) δ: 8.39 (s, 1H), 8.14 (dd, J=7.5, 1.3 Hz,1H), 7.97 (dd, J=8.2, 1.5 Hz, 1H), 7.32-7.40 (m, 1H), 7.17-7.25 (m, 4H),4.23 (d, J=12.9 Hz, 1H), 3.37 (s, 2H), 3.12-3.26 (m, 1H), 1.79-1.90 (m,1H), 1.61-1.73 (m, 1H), 1.51-1.61 (m, 1H), 1.47 (br. s., 2H), 1.38 (d,J=5.6 Hz, 2H), 0.96 (d, J=6.7 Hz, 6H). LC-MS: m/z 484.5 (M+H)⁺

Compound 468:2-amino-N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (DMSO-d₆) δ 10.30 (s, 1H), 8.48 (s, 1H), 7.90 (d, J=8.6 Hz, 1H),7.71 (d, J=9.7 Hz, 1H), 7.56-7.67 (m, 1H), 7.33 (s, 2H), 7.16 (d, J=8.6Hz, 2H), 7.09 (d, J=8.6 Hz, 2H), 4.16 (s, 1H), 4.06 (br. s., 1H), 3.21(br. s., 2H), 3.06 (br. s., 1H), 1.78 (dt, J=12.8, 6.2 Hz, 1H), 1.49(br. s., 1H), 1.36 (br. s., 3H), 1.27 (d, J=5.6 Hz, 2H), 0.89 (d, J=6.7Hz, 6H). LC-MS: m/z 484.5 (M+H)⁺

Compound 4862-amino-N-(4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (400 MHz, METHANOL-d₄) δ: 8.52 (s, 1H), 7.97 (dd, J=7.5, 1.3 Hz,1H), 7.73 (dd, J=8.6, 1.3 Hz, 1H), 7.56-7.64 (m, 1H), 7.15-7.26 (m, 4H),4.26 (br. s., 1H), 3.37 (s, 3H), 3.14-3.26 (m, 1H), 1.87-2.02 (m, 2H),1.43-1.68 (m, 9H). LC-MS: m/z 520.2 (M+H)⁺

Compound 493:2-amino-N-(4-(4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ 8.50 (s, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.96 (s,1H), 7.85 (d, J=9.4 Hz, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.26 (d, J=8.6 Hz,2H), 7.11 (d, J=6.7 Hz, 4H), 5.24 (s, 2H), 4.62 (br. s., 1H), 3.59 (br.s., 1H), 3.51 (br. s., 1H), 3.26 (br. s., 1H), 2.29 (br. s., 1H), 2.12(br. s., 1H), 1.89 (br. s., 1H), 1.76 (br. s., 1H). LC-MS: m/z 540.1(M+H)⁺

Compound 482:2-amino-N-(4-(4-hydroxy-4-(4,4,4-trifluorobutyl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (400 MHz, METHANOL-d₄) δ: 1.41-1.58 (m, 24H), 1.58-1.70 (m, 15H),2.08-2.22 (m, 9H), 3.37 (br. s., 6H), 7.20 (s, 19H), 7.60 (d, J=7.52 Hz,4H), 7.73 (dd, J=8.33, 1.34 Hz, 5H), 7.97 (dd, J=7.39, 1.21 Hz, 5H),8.52 (s, 4H). LC-MS: m/z 537.7 (M+H)⁺

General Procedure 58

Step A:

To a stirred suspension of tert-butyl4-(2-ethoxy-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate (10 g, 35mmol) in THF (100 mL), at r.t. was added a solution of lithium hydroxidemonohydrate (5.1 g, 122 mmol) in water (20 mL). After heating to refluxfor 3 h, the mixture was cooled to room temperature. The solvent wasevaporated, the residue was dissolved in water (50 mL) and extractedwith ether (3×50 mL), the aqueous layer was acidified to pH=3-5 byaddition of 1N HCl. Then the mixture was extracted with EtOAc (3×60 mL),the combined organic layers were washed with brine, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure to get58B. LC-MS: m/z 260.1 (M+H)⁺. ¹H NMR (CHLOROFORM-d) δ 3.84 (d, J=13.4Hz, 2H), 3.22 (t, J=11.3 Hz, 2H), 2.54 (s, 2H), 1.73 (d, J=12.6 Hz, 2H),1.49-1.58 (m, 2H), 1.47 (s, 9H)

Step B:

A mixture of 2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)aceticacid (1 g, 3.86 mol), N,O-dimethylhydroxylamine hydrochloride (412 mg,4.25 mmol), HBTU (1.6 g, 4.25 mmol), and DIPEA (1.5 g, 11.58 mmol) inDCM (20 mL) was stirred at room temperature for 3 hrs. The resultingmixture was washed water (3×20 mL), then with brine, dried over Na₂SO₄,evaporated, and purified by standard methods to get 58C. LC-MS: m/z 303(M+H)⁺

Step C:

A solution of 0.5 M ethynylmagnesium bromide in THF (10 mL, 5 mmol) wasadded to tert-butyl4-hydroxy-4-(2-(methoxy(methyl)amino)-2-oxoethyl)piperidine-1-carboxylate(500 mg, 1.65 mmol), then the mixture was heated to 50° C. for 1 hour.Then the reaction mixture was cooled to ambient temperature and wastreated with saturated aqueous ammonium chloride (20 mL), and thenheated to 50° C. for 1 hour. After this time, the reaction was cooled toambient temperature, extracted with ethyl acetate (20 mL), washed withbrine, dried over Na₂SO₄ and filtered. The filtrate was concentratedunder reduced pressure and purified by standard methods to afford 58D.LC-MS: m/z 329 (M+H)⁺

Step D:

To a solution of (E)-tert-butyl4-hydroxy-4-(4-(methoxy(methyl)amino)-2-oxobut-3-enyl)piperidine-1-carboxylate(250 mg, 0.762 mmol) in EtOH (10 mL) was added Hydrazine hydrate (50%,0.5 mL) and then the mixture was stirred at reflux for 1 h. Then thereaction mixture was cooled to room temperature and the solvent wasremoved under reduced pressure. The residue was dissolved in EtOAc (20mL) and washed with water (3×20 mL), the organic layer was collected andwashed with brine, dried over Na₂SO₄ and concentrated under reducedpressure to give 58E, which was used in the next step without furtherpurification. LC-MS: m/z 282.1 (M+H)⁺

Step E:

To a solution of tert-butyl4-((1H-pyrazol-3-yl)methyl)-4-hydroxypiperidine-1-carboxylate (120 mg,0.43 mmol) in DCM (10 mL) was added 4M HCl in dioxane (5 drops), thenthe mixture was stirred at room temperature for 10 min. The solvent wasthen removed and 58F was used in the next step without furtherpurification. LC-MS: m/z 182.1 (M+H)⁺

Step F:

To a solution of the corresponding 4-(aryl-4-sulfonamido)benzoic acid (1eq.) in DCM (5 mL) was added HBTU (1.2 eq.), DIPEA (3 eq.) and compound58F (1.0 eq.), sequentially at room temperature. The reaction mixturewas stirred at room temperature overnight. The mixture was poured intowater and extracted with DCM (20 mL) twice. The combined organic layerwas washed with brine and dried over anhy. Na₂SO₄. The combined organiclayer was concentrated in vacuo, and purified by standard methods togive 500.

Compound 500:N-(4-(4-((1H-pyrazol-3-yl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (400 MHz, METHANOL-d₄) δ: 9.11 (d, J=1.9 Hz, 1H), 9.03 (d, J=1.6Hz, 1H), 8.50 (dd, J=7.4, 1.2 Hz, 1H), 8.32 (d, J=8.6 Hz, 1H), 7.91 (t,J=7.9 Hz, 1H), 7.53 (s, 1H), 7.11-7.21 (m, 4H), 6.19 (s, 1H), 4.25 (br.s., 1H), 3.12-3.22 (m, 1H), 2.81 (s, 2H), 1.60 (br. s., 2H), 1.48 (br.s., 1H), 1.43 (br. s., 1H). LC-MS: m/z 493.4 (M+H)⁺

General Procedure 61

Step A

To the solution of ethyl 4-aminobenzoate (405 mg, 2.5 mmol) in DCM (15mL) were added pyridine (395 mg, 5.0 mmol) and5-oxo-5,6-dihydro-1,6-naphthyridine-8-sulfonyl chloride (61A, 600 mg,2.5 mmol). The mixture was stirred at 40° C. for 12 hrs, and then washedwith water. The solid was separated by filtration, washed with water,and dried under vacuum to provide 61B. LC-MS: m/z 374.1 (M+H)⁺

Step B

A mixture of ethyl 4-(5-hydroxy-1,6-naphthyridine-8-sulfonamido)benzoate61B (800 mg, 2.1 mmol) and NaOH (260 mg, 6.3 mmol) in methanol (30 mL)was stirred at 80° C. for 12 hrs. The mixture was cooled to r.t. andadjusted to pH=7 with aqueous HCl (1 N). The solid was separated byfiltration, washed with water, and dried under vacuum to provide 61C.LC-MS: m/z 346.1 (M+H)⁺

Step C

To 10 mL of phosphorus oxychloride was added4-(5-hydroxy-1,6-naphthyridine-8-sulfonamido)benzoic acid (61C, 450 mg,1.3 mol) with stirring. The mixture was refluxed for 12 hrs. Aftercooling, the mixture was concentrated and poured into ice water. Thesolid was separated by filtration, washed with water, and dried undervacuum to provide 61D. LC-MS: m/z 364.0 (M+H)⁺

Step D

A mixture of 4-(5-chloro-1,6-naphthyridine-8-sulfonamido)benzoic acid61D (400 mg) and Hydrazine hydrate (50 mg, 1.0 mmol) in THF (15 mL) wasstirred at 65° C. for 1 h. After cooling, the mixture was concentratedand poured into the ice water. The solid was separated by filtration,washed with water, and dried under vacuum to provide 61E, which was usedin the next step without further purification. LC-MS: m/z 360.1 (M+H)⁺

Step E: 4-(1,6-naphthyridine-8-sulfonamido)benzoic acid (61F)

A mixture of 4-(5-hydrazinyl-1,6-naphthyridine-8-sulfonamido)benzoicacid (400 mg, crude from last step) and Cupric sulfate (110 mg, 0.69mmol) in water (10 mL) was stirred at 70° C. for 2 hrs. After cooling,the mixture was filtered. The product was collected, washed with water,and dried under vacuum to provide 61F, which was used in the next stepwithout further purification. LC-MS: m/z 330.1 (M+H)⁺

Step F: Compound 513N-(4-(4-hydroxy-4-isobutylpiperidine-1-carbonyl)phenyl)-1,6-naphthyridine-8-sulfonamide

To the solution of 4-(1,6-naphthyridine-8-sulfonamido)benzoic acid 61F(350 mg) in DCM (15 mL) was added HBTU (644 mg, 1.7 mmol), TEA (222 mg,2.2 mmol) and 4-isobutylpiperidin-4-ol (204 mg, 1.3 mmol). The mixturewas stirred at r.t. for 1 h, and washed with water. The organic layerwas concentrated and purified by Prep-TLC (PE/EA=1/1) to provide 513. ¹HNMR (CHLOROFORM-d) δ 9.50 (br, 1H), 9.35 (br, 1H), 9.29 (br, 1H), 8.50(br, 1H), 8.20 (s, 1H), 7.79 (br, 1H), 7.18 (d, J=8.0 Hz, 2H), 7.08 (d,J=8.0 Hz, 2H), 4.30 (br, 1H), 3.47 (br, 3H), 2.04-1.98 (m, 4H),1.85-1.78 (m, 1H), 1.39 (d, J=5.6 Hz, 2H), 0.95 (d, J=6.8 Hz, 6H).LC-MS: m/z 469.2 (M+H)⁺

General Procedure 62

Step A

62B is prepared using procedures described herein.

Step B

To a solution of benzyl4-hydroxy-4-(2-methylallyl)piperidine-1-carboxylate 62B (2.9 g, 10 mmol)in 50 mL of DCM was added pyridine (2.4 g, 30 mmol) and chloromethylcarbonochloridate (1.9 g, 15 mmol). The resulting mixture was stirred at50° C. overnight. After removal of DCM, the residue was partitionedbetween water and EtOAc. The organic layer was washed with 2 N HCl,water and brine, dried over Na₂SO₄, concentrated, and purified bystandard methods to give 62C. LC-MS: m/z 382.1 (M+H)⁺.

Step C

A mixture of benzyl4-((chloromethoxy)carbonyloxy)-4-(2-methylallyl)piperidine-1-carboxylate62C (382 mg, 1.0 mmol) and potassium di-tert-butyl phosphate (496 mg, 2mmol) in DMF (15 mL) was stirred at 45° C. overnight. The solvent wasremoved under reduced pressure and the residue was partitioned betweenwater and EtOAc. The organic layer was washed with water and brine,dried over Na₂SO₄ and concentrated, then purified by standard methods toafford 62D. LC-MS: m/z 556.3 (M+H)⁺.

Step D

A mixture of benzyl4-4(((di-tert-butoxyphosphoryl)oxy)methoxy)carbonyl)oxy)-4-(2-methylallyl)piperidine-1-carboxylate62D (1.2 g, 2.2 mmol) and Pd on carbon in ethanol (20 mL) was stirred atr.t. under hydrogen atmosphere for 3 hrs. The solid was removed off byfiltration and the solvent was concentrated to give 62E, which was usedin the next step without further purification. LC-MS: m/z 424.5 (M+H)⁺.

Step E: (di-tert-butoxyphosphoryloxy)methyl4-isobutyl-1-(4-(quinoxaline-5-sulfonamido)benzoyl)piperidin-4-ylcarbonate (62F)

To a solution of 4-(quinoxaline-5-sulfonamido)benzoic acid (1 eq.) inDCM (5 mL) was added HBTU (1.2 eq.), DIPEA (3 eq.) and(di-tert-butoxyphosphoryloxy)methyl 4-isobutylpiperidin-4-yl carbonate62E (1.0 eq.), sequentially at room temperature. The reaction mixturewas stirred at room temperature overnight. The mixture was poured intowater and extracted with DCM (20 mL) twice. The combined organic layerwas washed with brine and dried over anhy. Na₂SO₄, concentrated invacuo, and purified by standard methods to afford 62F. LC-MS: m/z 735.3(M+H)⁺.

Step F: Compound 5274-isobutyl-1-(4-(quinoxaline-5-sulfonamido)benzoyl)piperidin-4-ylphosphonooxymethyl carbonate

To a solution of (di-tert-butoxyphosphoryloxy)methyl4-isobutyl-1-(4-(quinoxaline-5-sulfonamido)benzoyl)piperidin-4-ylcarbonate 62F (360 mg, 0.5 mmol) in DCM (15 mL) was added dropwise asolution of TFA (1 mL) in DCM (2 mL) at 0° C. and the mixture wasstirred at 0° C. for 1 h. The solvent was then removed under reducedpressure, and the residue was purified by standard methods to afford527. ¹H NMR (DMSO-d₆) M0.70 (br. s., 1H), 9.10 (s, d, J=8.0 Hz, 2H),8.51 (br. s., 1H), 8.38 (br. s., 1H), 7.99-7.77 (m, 1H), 7.17 (br. s.,2H), 7.09 (br. s., 2H), 5.26-5.49 (m, 2H), 4.06 (br. s., 1H), 3.25 (br.s., 2H), 2.97 (br. s., 1H), 2.14 (br. s., 1H), 1.99 (br. s., 1H), 1.74(br. s., 3H), 1.50 (br. s., 2H), 0.84 (d, J=5.9 Hz, 6H). LC-MS: m/z623.1 (M+H)⁺.

General Procedure 63

Step A

To a solution of 5-iodo-3-methylisothiazole (63A, 225 mg, 1.0 mmol) inTHF (10 mL) was added ethylmagnesium bromide (2N, 0.55 mL, 1.1 mmol) at0° C. under N₂ atmosphere. The reaction mixture was stirred at 0° C. for3 hrs, and then a solution of tert-butyl4-formylpiperidine-1-carboxylate (213 mg, 1.0 mmol) in THF (1 mL) wasadded dropwise to the above solution at −10° C. under N₂ atmosphere. Thereaction mixture was stirred at r.t. under N₂ overnight. The reactionmixture was quenched by sat. NH₄Cl solution, and the resulting mixturewas extracted with EtOAc twice, was washed with brine, dried overanhydrous Na₂SO₄, filtered and the filtrate was concentrated in vacuo toafford 63B. LC-MS: m/z 313.5 (M+H)⁺.

Step B

To a solution of tert-butyl4-(hydroxy(3-methylisothiazol-5-yl)methyl)piperidine-1-carboxylate (63B,60 mg, 0.192 mmol) in DCM (5 mL) was added DIPEA (28 mg, 0.212 mmol),followed by MsCl (24.3 mg, 0.212 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 0.5 h. Then the reaction mixture was allowed towarm to r.t. and stirred for additional 1 h. The mixture was extractedwith DCM (10 mL, twice). The combined organic phase was washed withbrine, dried over anhy. Na₂SO₄, filtered and the filtrate wasconcentrated in vacuo to afford 63C. LC-MS: m/z 331.1 (M+H)⁺.

Step C

To a solution of tert-butyl4-(chloro(3-methylisothiazol-5-yl)methyl)piperidine-1-carboxylate (63C,78 mg, 0.236 mmol) in DCM (0.5 mL) was added DBU (3 mL) at r.t. Thereaction mixture was stirred at 120° C. in microwave for 0.5 h. Then thereaction mixture was cooled to r.t., and was extracted with EtOAc (10mL, twice). The combined organic phase was washed with brine, dried overanhy. Na₂SO₄, filtered and the filtrate was concentrated in vacuo toafford 63D. ¹H NMR (CHLOROFORM-d) δ 6.82 (s, 1H), 6.44 (s, 1H), 3.51(dd, J=11.2, 5.3 Hz, 4H), 2.54 (t, J=5.7 Hz, 2H), 2.45 (d, J=12.6 Hz,3H), 2.38 (t, J=5.7 Hz, 2H), 1.49 (s, 9H). LC-MS: m/z 295.1 (M+H)⁺.

Step D

To a solution of tert-butyl4-((3-methylisothiazol-5-yl)methylene)piperidine-1-carboxylate (63D, 147mg, 0.5 mmol) in acetone (12 mL) and H₂O (2 mL) was added dropwise H₂SO₄(123 mg, 1.25 mmol) in H₂O (0.6 mL), followed with NBS (134 mg, 0.75mmol) at 0-5° C. The reaction mixture was stirred at 0-5° C. for 3 hrs.Then the reaction mixture was extracted with EtOAc (10 mL, twice). Thecombined organic phase was washed with brine, dried over anhy. Na₂SO₄,filtered, and the filtrate was concentrated in vacuo to afford 63E.LC-MS: m/z 391.1 (M+H)⁺.

Step E

To a solution of tert-butyl4-(bromo(3-methylisothiazol-5-yl)methyl)-4-hydroxypiperidine-1-carboxylate(63E, 58 mg, 0.15 mmol) and AIBN (4.9 mg, 0.03 mmol) in toluene (5 mL)was added Tributyltin hydride (65.1 mg, 0.223 mmol) at r.t. under N₂.The reaction mixture was stirred at 90° C. for 8 h, when TLC showed thatthe reaction was complete. The reaction mixture was concentrated invacuo to afford 63F. ¹H NMR (CHLOROFORM-d) δ 6.82 (s, 1H), 3.84 (s, 2H),3.16 (s, 2H), 3.06 (s, 2H), 2.48 (s, 3H), 1.77 (s, 2H), 1.58 (s, 2H),1.47 (s, 9H) LC-MS: m/z 313.2 (M+H)⁺.

Step F:

To a solution of tert-butyl4-hydroxy-4-((3-methylisothiazol-5-yl)methyl)piperidine-1-carboxylate(63F, 55 mg) in DCM (5 mL), was added TFA (1 mL), the reaction mixturewas stirred at room temperature for about 2 hours, when LCMS detected nos.m. The reaction mixture was concentrated to afford the desired product63G, which was used for the next step directly without furtherpurification. LC-MS: m/z 213.2 (M+H)⁺.

The following compounds were prepared according to General Procedure 63.

Step G: Compound 511N-(4-(4-hydroxy-4-((3-methylisothiazol-5-yl)methyl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

To a solution of 4-(quinoxaline-5-sulfonamido)benzoic acid (0.18 mmol)in DCM (5 mL) was added HBTU (80 mg, 0.22 mmol), DIPEA (70 mg, 0.54mmol) and 4-((3-methylisothiazol-5-yl)methyl)piperidin-4-ol (7, 38 mg,0.18 mmol), sequentially at room temperature. The reaction mixture wasstirred at room temperature for 1 hour. The mixture was poured intowater and extracted with EtOAc (20 mL) twice. The combined organic layerwas washed with brine and dried over anhy. Na₂SO₄, concentrated invacuo, and purified by standard methods to afford 511. ¹H NMR(CHLOROFORM-d) δ 9.08 (s, 2H), 8.45 (dd, J=7.3, 1.3 Hz, 1H), 8.36 (dd,J=8.5, 1.4 Hz, 1H), 8.01 (s, 1H), 7.85 (dd, J=8.4, 7.4 Hz, 1H), 7.19 (d,J=8.4 Hz, 2H), 7.09 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 4.40 (s, 1H), 3.38(m, 3H), 3.07 (s, 2H), 2.50 (s, 3H), 1.53 (s, 4H). LC-MS: m/z 524.52(M+H)⁺

The following compounds were prepared according to General Procedure 6,Step C).

Compound 473:N-(4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)-3-(difluoromethoxy)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.31 (s, 1H), 8.22 (d, J=8.3 Hz, 1H), 8.12 (d,J=6.7 Hz, 1H), 8.04 (s, 1H), 7.57 (t, J=7.8 Hz, 1H), 7.09 (d, J=7.8 Hz,1H), 6.92-7.04 (m, 2H), 6.35 (t, J=72 Hz, 1H), 4.42 (br. s., 1H), 3.20(br. s., 3H), 1.96 (br. s., 2H), 1.55-1.70 (m, 7H), 1.43-1.53 (m, 2H).LC-MS: m/z 576.1 (M+H)⁺

Compound 477:N-(3-cyano-4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ 1.55-1.70 (m, 9H) 1.87-2.04 (m, 2H) 3.12-3.33(m, 2H) 3.43 (br. s., 1H) 4.43 (d, J=12.63 Hz, 1H) 7.24 (d, J=8.33 Hz,1H) 7.36-7.48 (m, 2H) 7.60 (t, J=7.79 Hz, 1H) 8.14 (d, J=7.52 Hz, 1H)8.21-8.32 (m, 2H) 9.33 (s, 1H). LC-MS: m/z 535.1 (M+H)⁺

Compound 469:N-(4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)-3-fluorophenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ 1.31 (s, 1H) 1.51-1.72 (m, 8H), 1.87-2.04 (m,2H), 3.20 (dd, J=12.22, 9.27 Hz, 2H), 3.37 (s, 1H), 4.31 (d, J=13.43 Hz,1H), 6.95-7.08 (m, 2H), 7.14 (t, J=8.06 Hz, 1H), 7.62 (t, J=7.79 Hz,1H), 8.17 (dd, J=7.52, 1.07 Hz, 1H), 8.37 (dd, J=8.19, 0.94 Hz, 1H),9.48 (s, 1H). LC-MS: m/z 528.1 (M+H)⁺

Compound 491:2-amino-N-(3-cyano-4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-6-fluorobenzo[d]thiazole-4-sulfonamide

¹H NMR (400 MHz, METHANOL-d₄) δ: 1.47-1.69 (m, 9H), 1.86-2.07 (m, 2H),3.08-3.20 (m, 1H), 3.20-3.29 (m, 1H), 3.36-3.47 (m, 1H), 4.37 (d,J=12.89 Hz, 1H), 7.37 (d, J=8.33 Hz, 1H), 7.44-7.62 (m, 3H), 7.68 (dd,J=7.92, 2.55 Hz, 1H). LC-MS: m/z 568.1 (M+H)⁺

Compound 483:2-amino-N-(4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)-3-fluorophenyl)-6-fluorobenzo[d]thiazole-4-sulfonamide

¹H NMR (400 MHz, METHANOL-d₄) δ: 1.45-1.73 (m, 9H), 1.87-2.05 (m, 2H),3.17-3.29 (m, 2H), 3.37 (s, 1H), 4.33 (d, J=13.16 Hz, 1H), 7.03 (d,J=9.40 Hz, 2H), 7.21 (t, J=7.66 Hz, 1H), 7.52 (dd, J=8.60, 2.69 Hz, 1H),7.66 (dd, J=8.06, 2.69 Hz, 1H). LC-MS: m/z 561.1 (M+H)⁺

Compound 459:N-(4-(4-((2,2-difluorocyclopropyl)methyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.31 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 8.10 (d,J=6.7 Hz, 1H), 7.94 (s, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.16-7.25 (m, J=8.3Hz, 2H), 7.05-7.16 (m, J=8.6 Hz, 2H), 4.38 (br. s., 1H), 3.35 (br. s.,2H), 3.23 (br. s., 1H), 1.60 (s, 3H), 1.63 (s, 2H), 1.48-1.57 (m, 4H),0.91-1.02 (m, 1H). LC-MS: m/z 508.6 (M+H)⁺

Compound 454:4-hydroxy-N-(4-(4-hydroxy-4-(4,4,4-trifluorobutyl)piperidine-1-carbonyl)phenyl)quinazoline-8-sulfonamide

¹H NMR (DMSO-d₆) δ 8.35 (td, J=7.8, 1.5 Hz, 2H), 8.26 (s, 1H), 7.62 (t,J=7.8 Hz, 1H), 7.19 (d, J=8.4 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 4.37 (s,1H), 4.05 (s, 1H), 3.0-3.3 (m, 3H), 2.21 (m, 2H), 1.36-1.53 (m, 8H).LC-MS: m/z 539.1 (M+H)⁺

Compound 453

¹H NMR (400 MHz, MeOD) δ: 8.40 (td, J=7.8, 1.5 Hz, 2H), 8.28 (s, 1H),7.59 (t, J=7.8 Hz, 1H), 7.24 (s, 4H), 4.28 (s, 1H), 3.38 (d, J=8.4 Hz,2H), 3.20 (d, J=3.6 Hz, 1H), 2.34-2.20 (m, 2H), 1.66-1.72 (m, 4H),1.45-1.55 (m, 2H). LC-MS: m/z 525.5 (M+H)⁺

Compound 455:N-(4-(4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-4-hydroxyquinazoline-8-sulfonamide

¹H NMR (CHLOROFORM-d) δ 8.41 (dt, J=7.7, 1.8 Hz, 2H), 8.28 (s, 1H), 7.59(t, J=7.8 Hz, 1H), 7.42 (t, J=6.8 Hz, 1H), 7.31-7.24 (m, 4H), 7.18 (pd,J=8.5, 3.6 Hz, 2H), 4.50 (s, 1H), 3.53 (s, 2H), 3.30-3.20 (m, 1H), 2.22(d, J=57.2 Hz, 2H), 1.73 (d, J=58.7 Hz, 2H). LC-MS: m/z 541.42 (M+H)⁺

The following compounds were prepared according to General Procedure 8,step E.

Compound 478:N-(4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)-3-fluorophenyl)quinoxaline-5-sulfonamide

¹H NMR (400 MHz, CHLOROFORM-d) δ 1.45-1.67 (m, 10H), 1.84-2.04 (m, 2H),3.08-3.30 (m, 2H), 3.34 (br. s., 1H), 4.39 (d, J=13.16 Hz, 1H),6.73-6.86 (m, 1 H), 6.98 (dd, J=10.75, 1.61 Hz, 1H), 7.13 (t, J=7.79 Hz,1H), 7.89 (dd, J=8.33, 7.52 Hz, 1H), 8.14 (s, 1H), 8.39 (dd, J=8.46,1.21 Hz, 1H), 8.49 (dd, J=7.25, 1.34 Hz, 1H), 9.03-9.12 (m, 2H). LC-MS:m/z 523.5 (M+H)⁺

Compound 464:N-(4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)-3-(difluoromethoxy)phenyl)quinoxaline-5-sulfonamide

¹H NMR (DMSO-d₆) δ 10.84 (br. s., 1H), 9.12 (dd, J=7.5, 1.9 Hz, 2H),8.52 (d, J=6.2 Hz, 1H), 8.35-8.42 (m, 1H), 7.97-8.05 (m, 1H), 7.11 (br.s., 1H), 7.00 (s, 1H), 6.99 (t, J=72 Hz, 1H), 6.93-6.97 (m, 1H), 4.42(s, 1H), 4.12 (d, J=12.9 Hz, 1H), 3.12 (br. s., 1H), 3.01 (br. s., 1H),2.93 (br. s., 1H), 1.87 (br. s., 2H), 1.58 (t, J=18.9 Hz, 3H), 1.47 (br.s., 2H), 1.25-1.27 (br. s., 2H), 1.26 (m, 2H). LC-MS: m/z 535.32 (M+H)⁺

The following compounds were prepared according to General Procedure 44,Step E.

Compound 452:(E)-2-amino-N-(4-(4-hydroxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (DMSO-d₆) δ 7.68-7.83 (m, 2H), 7.17-7.33 (m, 4H), 7.07 (t, J=7.8Hz, 1H), 5.89 (d, J=15.6 Hz, 1H), 5.71 (dt, J=15.5, 7.0 Hz, 1H), 4.28(br. s., 1H), 3.43 (br. s., 1H), 3.37 (s, 1H), 3.25 (d, J=7.8 Hz, 1H),2.83-3.06 (m, 2H), 1.64 (br. s., 3H), 1.48 (br. s., 1H). LC-MS: m/z555.5 (M+H)⁺

Compound 451:(E)-4-hydroxy-N-(4-(4-hydroxy-4-(4,4,4-trifluorobut-1-enyl)piperidine-1-carbonyl)phenyl)quinazoline-8-sulfonamide

¹H NMR (400 MHz, MeOD) δ: 8.42 (dd, J=7.9, 1.5 Hz, 1H), 8.34 (dd, J=7.7,1.5 Hz, 1H), 8.20 (s, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.44 (s, 1H),7.11-7.23 (m, 4H), 5.72-5.82 (m, 1H), 5.59-5.72 (m, 1H), 3.42 (br. s.,2H), 3.37 (s, 1H), 2.82 (dd, J=10.3, 7.1 Hz, 2H), 1.66 (br. s., 2H),1.49 (br. s., 2H). LC-MS: m/z 537.6 (M+H)⁺

The following compounds were prepared according to General Procedure 46,Step E.

Compound 445:2-amino-N-(4-(4-hydroxy-4-(4,4,4-trifluorobutyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (400 MHz, MeOD) δ: 1.28-1.41 (m, 4H), 1.44-1.59 (m, 23H),1.60-1.72 (m, 1411), 2.09-2.23 (m, 9H), 3.22 (br. s., 5H), 3.40 (br. s.,711), 4.25 (br. s., 4H), 7.07 (t, J=7.79 Hz, 5H), 7.19-7.25 (m, 19H),7.73 (dd, J=7.79, 1.07 Hz, 5H), 7.79 (dd, J=7.79, 1.07 Hz, 5H). LC-MS:m/z 543.7 (M+H)⁺

Compound 457:2-amino-N-(4-(4-hydroxy-4-(3,3,3-trifluoropropyl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (400 MHz, MeOD) δ: 7.79 (dd, J=7.8, 1.1 Hz, 1H), 7.73 (dd, J=7.8,1.0 Hz, 1H), 7.27-7.19 (m, 4H), 7.07 (t, J=7.8 Hz, 1H), 4.28 (s, 1H),3.42 (s, 1H), 3.26-3.12 (m, 2H), 2.34-2.21 (m, 2H), 1.70 (dd, J=11.4,5.6 Hz, 2H), 1.49 (s, 2H), 1.38 (t, J=6.2 Hz, 2H). LC-MS: m/z 529.5(M+H)⁺

Compound 447:2-amino-N-(4-(4-(2,3-difluorophenyl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ 7.76 (ddd, J=16.2, 7.8, 1.2 Hz, 2H), 7.45-7.39(m, 1H), 7.31-7.21 (m, 4H), 7.17 (tdd, J=11.4, 7.4, 3.7 Hz, 2H), 7.07(t, J=7.8 Hz, 1H), 4.51 (d, J=12.2 Hz, 1H), 3.54 (s, 2H), 3.27 (s, 1H),2.23 (d, J=52.7 Hz, 2H), 1.74 (dd, J=67.6, 12.8 Hz, 2H). LC-MS: m/z545.73 (M+H)⁺

Compound 4632-amino-N-(4-(4-(3,3-difluorobutyl)-4-hydroxypiperidine-1-carbonyl)phenyl)-6-fluorobenzo[d]thiazole-4-sulfonamide

¹H NMR (DMSO-d₆) δ 10.26 (s, 1H), 7.94 (d, J=5.6 Hz, 1H), 7.90 (s, 2H),7.45 (dd, J=8.9, 2.7 Hz, 1H), 7.21-7.27 (m, J=8.6 Hz, 2H), 7.10-7.17 (m,J=8.6 Hz, 2H), 4.43 (s, 1H), 4.10 (br. s., 1H), 3.26 (br. s., 2H), 3.08(br. s., 1H), 1.89 (br. s., 2H), 1.59 (t, J=18.8 Hz, 3H), 1.49 (d,J=11.0 Hz, 2H), 1.39 (br. s., 2H), 1.24-1.27 (m, 2H). LC-MS: m/z 543.5(M+H)⁺

The following compounds were prepared according to General Procedure 48.

Compound 515:N-(4-(4-hydroxy-4-(isothiazol-5-yl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (400 MHz, MeOD) δ: 1.83 (br. s., 1H), 2.00 (br. s., 3H), 3.50(br. s., 3H), 4.46 (br. s., 1H), 7.13-7.30 (m, 5H), 7.58 (t, J=7.79 Hz,1H), 8.13 (dd, J=7.66, 0.94 Hz, 1H), 8.28-8.43 (m, 2H), 9.49 (s, 1H).LC-MS: m/z 501.4 (M+H)⁺

Compound 528N-(4-(4-hydroxy-4-(3-methylisothiazol-5-yl)piperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.31 (s, 1H), 8.20 (d, J=8.1 Hz, 1H), 8.10 (d,J=7.5 Hz, 1H), 7.96 (s, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.23 (d, J=8.5 Hz,2H), 7.13 (d, J=8.5 Hz, 2H), 6.89 (s, 1H), 4.55 (s, 1H), 3.69-3.23 (m,3H), 2.56 (s, 3H), 2.19-1.69 (m, 4H). LC-MS: m/z 515.48 (M+H)⁺

Compound 518:N-(4-(4-hydroxy-4-(3-methylisothiazol-5-yl)piperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.12 (d, J=1.8 Hz, 1H), 9.03 (d, J=1.8 Hz, 1H),8.51 (dd, J=7.4, 1.3 Hz, 1H), 8.32 (dd, J=8.5, 1.3 Hz, 1H), 7.92 (dd,J=8.4, 7.5 Hz, 1H), 7.29-7.16 (m, 4H), 7.01 (s, 1H), 4.44 (s, 1H), 3.48(s, 2H), 3.24 (s, 1H), 2.42 (s, 3H), 1.89 (m, 4H). LC-MS: m/z 510.5(M+H)⁺

Compound 480:N-(4-(4-(4-chlorothiazol-5-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.32 (s, 1H), 8.61 (s, 1H), 8.20 (dd, J=8.1, 1.0Hz, 1H), 8.11 (dd, J=7.6, 1.0 Hz, 1H), 7.97 (s, 1H), 7.55 (t, J=7.8 Hz,1H), 7.26-7.19 (m, 2H), 7.16-7.10 (m, 2H), 4.60 (s, 1H), 3.63 (s, 1H),3.36 (d, J=63.1 Hz, 2H), 2.30 (s, 2H), 1.97 (s, 2H). LC-MS: m/z 535.32(M+H)⁺

Compound 516:N-(4-(4-(4-chloroisothiazol-5-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)quinoxaline-5-sulfonamide

¹H NMR (CHLOROFORM-d) δ 9.08 (s, 2H), 8.46 (d, J=6.7 Hz, 1H), 8.36 (d,J=8.3 Hz, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.86 (t, J=7.8 Hz, 1H), 7.24(d, J=6.2 Hz, 2H), 7.06-7.18 (m, 2H), 4.60 (br. s., 1H), 3.62 (br. s.,1H), 3.45-3.56 (m, 1H), 3.23 (br. s., 1H), 2.37 (br. s., 1H), 2.19 (s,1H), 1.87 (br. s., 2H). LC-MS: m/z 530.5 (M+H)⁺

Compound 522:N-(4-(4-(4-chloroisothiazol-5-yl)-4-hydroxypiperidine-1-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide

¹H NMR (METHANOL-d₄) δ 9.50 (s, 1H), 8.34 (dd, J=8.2, 0.9 Hz, 1H), 8.29(s, 1H), 8.13 (dd, J=7.8, 1.1 Hz, 1H), 7.58 (t, J=7.9 Hz, 1H), 7.17-7.27(m, 4H), 4.52 (br. s., 1H), 3.50 (br. s., 2H), 3.21 (br. s., 1H), 2.72(br. s., 1H), 2.44 (br. s., 1H), 2.30 (br. s., 1H), 1.70 (br. s., 2H).LC-MS: m/z 535.5 (M+H)⁺

The following compounds were prepared according procedures describedherein.

Compound LC-MS: m/z ID Structure (M + H)⁺ 492

530.6 505

525.6 526

628.6 477

535.6 471

469.6 510

531.0 474

505.6 472

510.6 503

521.6 504

530.7 507

507.6 490

519.6 467

485.6 481

536.1 509

536.1 485

530.7 487

529.6 470

519.6 496

510.6 506

526.6 495

515.6 446

512.0 484

524.6 476

518.7 466

524.6 488

529.6 450

498.6 449

457.6 460

485.6 475

513.6 524

554.6 525

549.5 494

545.0 529

473.6 517

496.1 523

577.6

Having thus described several aspects of several embodiments, it is tobe appreciated various alterations, modifications, and improvements willreadily occur to those skilled in the art. Such alterations,modifications, and improvements are intended to be part of thisdisclosure, and are intended to be within the spirit and scope of theinvention. Accordingly, the foregoing description and drawings are byway of example only.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: A is aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substituted,and the aryl or heteroaryl is optionally fused to an optionallysubstituted carbocyclyl or an optionally substituted heterocyclyl; X isselected from —NH—S(O)₂—, —S(O)₂—NH—, —NH—S(O)₂—CH₂—, —CH₂—S(O)—NH—,—NH—S(O)—CH₂—, —NH—S(O)—, —S(O)—NH—, or —CH₂—S(O)₂—NH—; Y is C(H) or N;provided that no more than two Y groups are N; R^(1a) is hydroxyl,—CH₂OH, —CHO, —CO₂H, —N(R^(10a))₂, —CO₂—C₁₋₆ alkyl, —OP(═O)(OH)₂, or—OCO₂—CH₂—OP(═O)(OH)₂; R^(1b) is C₁₋₈ alkyl optionally substituted withone to four R⁵ groups; C₁₋₈ alkenyl optionally substituted with one tofour R⁵ groups; cycloalkyl; heterocycle; aryl; heteroaryl;cycloalkylalkyl; cycloalkylalkenyl; heterocyclylalkyl;heterocyclylalkenyl; aralkyl; aralkenyl; heteroaralkyl; heteroaralkenyl;or —OH, with the proviso that when R^(1a) is OH, R^(1b) is not OH;wherein each cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl,cycloalkylalkenyl, heterocyclylalkyl, heterocyclylalkenyl, aralkyl,aralkenyl, heteroaralkyl, or heteroaralkenyl is optionally substituted;each R² is independently selected from halo, alkyl, CN, OH, and alkoxy,wherein said alkyl or alkoxy is optionally substituted with one to fourR⁵ groups; or two adjacent R² groups are taken together with the ringatoms they are attached to form a 5- or 6-membered carbocyclic, aryl,heterocyclic or heteroaryl ring; each R⁴ is independently selected fromhalo, alkyl, alkoxy, haloalkyl, haloalkoxy and hydroxyl; each R⁵ isindependently selected from halo, OH, C₁₋₆ alkoxy, CN, NH₂, —SO₂—C₁₋₆alkyl, —NH(C₁₋₆ alkyl), and —N(C₁₋₆ alkyl)₂; each R^(10a) isindependently selected from hydrogen or C₁₋₆ alkyl; n is 0, 1, 2 or 3;and m is 0, 1 or 2; provided that a compound of Formula (I) is not thefollowing: (1)4-[[4-hydroxy-4-(4-methylphenyl)-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;(2)4-[[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;(3)4-[[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;(4)4-[[4-(2-fluoro-5-methylphenyl)-4-hydroxy-1-piperidinyl]carbonyl]-N-2-thiazolyl-benzenesulfonamide;(5) 4-phenyl-1-[4-[(phenylamino)sulfonyl]benzoyl]-4-piperidinecarboxylicacid methyl ester; (6)1-[4-[[(2-methylphenyl)amino]sulfonyl]benzoyl]-4-phenyl-4-piperidinecarboxylicacid methyl ester; or (7)N-(4-fluorophenyl)-4-[[4-hydroxy-4-(methoxymethyl)-1-piperidinyl]carbonyl]-benzenesulfonamide.2. The compound of claim 1, wherein the compound is a compound ofFormula (Ia):


3. A compound of Formula (Ib):

or a pharmaceutically acceptable salt thereof, wherein: A is aryl orheteroaryl, wherein the aryl or heteroaryl is optionally substituted,and the aryl or heteroaryl is fused to an optionally substitutedcarbocyclyl or an optionally substituted heterocyclyl; R^(1b) is C₁₋₈alkyl optionally substituted with one to four R⁵ groups; C₁₋₈ alkenyloptionally substituted with one to four R⁵ groups; cycloalkyl;heterocycle; aryl; heteroaryl; cycloalkylalkyl; cycloalkylalkenyl;heterocyclylalkyl; heterocyclylalkenyl; aralkyl; aralkenyl;heteroaralkyl; heteroaralkenyl; or —OH, with the proviso that whenR^(1a) is OH, R^(1b) is not OH; wherein each cycloalkyl, heterocycle,aryl, heteroaryl, cycloalkylalkyl, cycloalkylalkenyl, heterocyclylalkyl,heterocyclylalkenyl, aralkyl, aralkenyl, heteroaralkyl, orheteroaralkenyl is optionally substituted; each R² is independentlyselected from halo, alkyl, CN, OH, and alkoxy, wherein said alkyl oralkoxy is optionally substituted with one to four R⁵ groups; or twoadjacent R² groups are taken together with the ring atoms they areattached to form a 5- or 6-membered carbocyclic, aryl, heterocyclic orheteroaryl ring; each R⁴ is independently selected from halo, alkyl,alkoxy, haloalkyl, haloalkoxy and hydroxyl; each R⁵ is independentlyselected from halo, OH, C₁₋₆ alkoxy, CN, NH₂, —SO₂—C₁₋₆ alkyl, —NH(C₁₋₆alkyl), and —N(C₁₋₆ alkyl)₂; n is 0, 1, 2 or 3; and m is 0, 1 or
 2. 4.The compound of claim 3, wherein A is:


5. The compound of claim 3, wherein the compound is a compound ofFormula (II):


6. The compound of claim 3, wherein the compound is a compound ofFormula (III):


7. The compound of claim 3, wherein the compound is a compound ofFormula (IV):


8. The compound of claim 3, wherein R^(1b) is C₁₋₈ alkyl optionallysubstituted with one to four R⁵ groups; aryl; heteroaryl; aralkyl; orheteroaralkyl; wherein each aryl; heteroaryl; aralkyl; or heteroaralkyl;is optionally substituted.
 9. The compound of claim 8, wherein eacharyl; heteroaryl; aralkyl; or heteroaralkyl is optionally substitutedwith halo, C₁₋₆ alkyl, —OH, C₁₋₆ alkoxy, —CN, —NH₂, —SO₂—C₁₋₆ alkyl,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, aryl, haloalkyl, or haloalkoxy. 10.The compound of claim 3, wherein R^(1b) is C₁₋₈ alkyl optionallysubstituted with one to four R⁵ groups.
 11. The compound of claim 3,wherein R⁵ is fluoro, —OH, or —SO₂—CH₃.
 12. The compound of claim 3,wherein R^(1b) is phenyl, optionally substituted with chloro, fluoro,bromo, methyl, ethyl, —CN, difluoromethyl, trifluoromethyl, —OCF₃,—SO₂—CH₃, or —OCH₃.
 13. The compound of claim 1, wherein the compound ofFormula (I) is selected from Compounds 100-529 of Table
 1. 14. Apharmaceutical composition comprising a compound of claim 1 or apharmaceutical acceptable salt thereof and a pharmaceutically acceptablecarrier.
 15. A method of modulating PKM2 activity in a subject in needthereof, the method comprising administering to said subject apharmaceutical composition of claim
 14. 16. A method of treating acancer associated with PKM2 activity in a subject in need thereof, themethod comprising administering to the subject a pharmaceuticalcomposition of claim
 14. 17. Use of a pharmaceutical composition ofclaim 14 in the manufacture of a medicament for modulating PKM2activity.
 18. Use of a pharmaceutical composition of claim 14 in themanufacture of a medicament for treating a cancer associated with PKM2activity.
 19. A method for increasing the lifetime of the red bloodcells (RBCS) in need thereof comprising contacting blood with aneffective amount of (1) a compound of claim 1 or a pharmaceuticallyacceptable salt thereof; or (2) a composition of claim
 14. 20. Themethod of claim 19, wherein the compound is added directly to wholeblood or packed cells extracorporeally.
 21. The method of claim 19,wherein the pharmaceutical composition is administered to a subject inneed thereof.
 22. A method for regulating 2,3-diphosphoglycerate levelsin blood in need thereof comprising contacting blood an effective amountof (1) a compound of claim 1; or (2) a composition of claim
 14. 23. Amethod for treating hereditary non-spherocytic haemolytic anemiacomprising administering to a subject in need thereof a therapeuticallyeffective amount of an effective amount of (1) a compound of claim 1; or(2) a pharmaceutically acceptable composition of claim
 14. 24. A methodfor treating sickle cell anemia comprising administering to a subject inneed thereof a therapeutically effective amount of an effective amountof (1) a compound of claim 1; or (2) a pharmaceutically acceptablecomposition of claim 14.